Next Article in Journal
Association Analysis of Noncoding Variants in Neuroligins 3 and 4X Genes with Autism Spectrum Disorder in an Italian Cohort
Next Article in Special Issue
Assessing Heterogeneity of Osteolytic Lesions in Multiple Myeloma by 1H HR-MAS NMR Metabolomics
Previous Article in Journal
Why Are Omics Technologies Important to Understanding the Role of Nutrition in Inflammatory Bowel Diseases?
Previous Article in Special Issue
Cancer Cell Colonisation in the Bone Microenvironment
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 17
Issue 10
10.3390/ijms17101764
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

What Is Breast in the Bone?

by
Carrie S. Shemanko
*,
Yingying Cong
and
Amanda Forsyth
Department of Biological Sciences and Arnie Charbonneau Cancer Institute, 2500 University Dr, NW, University of Calgary, Calgary, AB T2N 1N4, Canada
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2016, 17(10), 1764; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101764
Submission received: 1 September 2016 / Revised: 11 October 2016 / Accepted: 14 October 2016 / Published: 22 October 2016
(This article belongs to the Special Issue Cellular and Molecular Mechanisms of Bone Metastasis)
Browse Figures
Versions Notes

Abstract

:
The normal developmental program that prolactin generates in the mammary gland is usurped in the cancerous process and can be used out of its normal cellular context at a site of secondary metastasis. Prolactin is a pleiotropic peptide hormone and cytokine that is secreted from the pituitary gland, as well as from normal and cancerous breast cells. Experimental and epidemiologic data suggest that prolactin is associated with mammary gland development, and also the increased risk of breast tumors and metastatic disease in postmenopausal women. Breast cancer spreads to the bone in approximately 70% of cases with advanced breast cancer. Despite treatment, new bone metastases will still occur in 30%–50% of patients. Only 20% of patients with bone metastases survive five years after the diagnosis of bone metastasis. The breast cancer cells in the bone microenvironment release soluble factors that engage osteoclasts and/or osteoblasts and result in bone breakdown. The breakdown of the bone matrix, in turn, enhances the proliferation of the cancer cells, creating a vicious cycle. Recently, it was shown that prolactin accelerated the breast cancer cell-mediated osteoclast differentiation and bone breakdown by the regulation of breast cancer-secreted proteins. Interestingly, prolactin has the potential to affect multiple proteins that are involved in both breast development and likely bone metastasis, as well. Prolactin has normal bone homeostatic roles and, combined with the natural “recycling” of proteins in different tissues that can be used for breast development and function, or in bone function, increases the impact of prolactin signaling in breast cancer bone metastases. Thus, this review will focus on the role of prolactin in breast development, bone homeostasis and in breast cancer to bone metastases, covering the molecular aspects of the vicious cycle.

Graphical Abstract

1. Introduction

“What is bred in the bone will not come out of the flesh” (based on the proverb, England (in Latin) circa 1290). Essentially this has been interpreted to mean that what is inherited, cannot be concealed. The normal developmental pathways contribute to both normal cell and tissue function, but when misregulated during cellular transformation and cancerous progression, these pathways can function inappropriately and with great harm. “What is breast in the bone” refers to the innate signal transduction pathways in the breast that can influence bone biology inappropriately when transformed breast cells migrate to the bone. In particular, this review refers to the roles of prolactin (PRL) signaling that contribute to normal mammary gland function, which are subverted in cancer to contribute to the disease process. We recently discovered that breast cancer cells that migrated to the bone carry the PRL-receptor (PRLR) and that PRL signaling to breast cancer cells advances osteolytic osteoclast differentiation via the production of a soluble factor that modulates the bone [1]. Interestingly, breast cancer cells secrete bone modulating factors most likely because they are produced normally in the breast for breast developmental processes: a number of these factors are PRL-regulated.
PRL and its receptor have essential roles in mammary gland development, particularly maintenance of luminal progenitors and the final functional differentiation of the breast with the production of milk-secretory alveolar cells [2,3,4]. The predominant pathway associated with this differentiation has been Janus kinase-2 (JAK2) [5,6] and signal transducer and activator of transcription-(STAT)-5a (STAT5a) [7,8,9].
The effects of PRL on breast cancer and metastasis are not fully elucidated, and reports appear conflicting due to our lack of understanding of PRL biology. High levels of local [10] or serum PRL [10,11] are tumorigenic in mice. Large prospective human studies identified an association of high PRL serum levels with breast cancer risk [12,13]. Elevated serum levels of PRL at pregnancy may explain in part the increase in breast cancer risk that occurs over the short-term post-pregnancy [14]. In breast cancer patients, high PRL is associated with an overall worse survival [15,16,17] and with an increase in the occurrence of breast cancer metastasis [18,19,20]. The PRLR has been reported to be part of a poor gene signature [21] and is associated with poor prognosis [21,22]. Therefore, there are reproducible associations, in humans, of increased breast cancer risk, progression, metastases and treatment resistance with increased PRL and the PRLR.
In contrast, in vitro data have demonstrated both invasive [23] and invasive suppressive properties [24,25] of PRL signaling, and a gene signature developed from xenografted T47D cells identified a gene signature associated with good prognosis [26]. Recent large human studies have demonstrated that PRL or PRL receptor expression or a gene signature of PRL, PRLR, JAK2 and STAT5a is associated with a good prognosis [27,28]. It is becoming apparent that the biology of PRL signaling is very complex [29] and that the microenvironment can play an important role in PRL pathway selection and response [30,31,32].
Contributing to PRL signaling complexity are two major sources of PRL, endocrine and autocrine/paracrine [33,34], the second of which helps understand the historical example of the poor response of patients treated with bromocriptine, which interferes with PRL secretion from the pituitary gland. PRL is very specific in its binding to the PRLR [35,36], although other related hormones will interact with the PRLR, such as growth hormone and placental lactogen. Constitutively-active PRLR variants have been identified [37], although not in association with breast cancer [38]. There are multiple PRLR isoforms that differ in their signaling capacity and function [29]. It is clear that PRL signaling is intricate at many molecular levels.
Approximately 70%–80% of advanced breast cancer patients will experience a metastasis to the bone [39,40], and this severely impacts their quality of life and can lead to death. It represents an essential area of study that will also impact our understanding of latent and active metastases.

2. Breast Cancer Bone Metastases

2.1. Vicious Cycle

The majority of breast cancer patients with bone metastases exhibit primarily osteolytic (bone destructive) lesions (80%–90%), although a small percentage (10%–20%) of patients exhibit primarily osteoblastic (bone building) lesions [41]. Breast cancer cells secrete soluble factors that act on osteoblasts or osteoclasts to ultimately stimulate osteoclast cell differentiation in lytic lesions. The osteoclasts then degrade the bone, which releases stored growth factors that stimulate breast cancer cell proliferation. The mitogenic factors, such as IGF-1, TGF-β and calcium, are stored during bone formation, and their action on the tumor cells perpetuates a vicious osteolytic cycle of tumor cell growth and osteolysis (Figure 1) [42]. The weakening of bone at the sites of metastasis puts the patients at risk of severe bone pain, bone breakage, spinal compression and hypercalcemia that result in pain and death [43]. The signaling pathways that feed into the vicious cycle have remained to be completely identified. Recently, a new PRL-based mechanism by which PRL-treated breast cancer cell-secreted factors directly promote the differentiation of functional osteoclast cells capable of bone resorption was identified, which likely is responsible for the observed acceleration of clinical detection of bone metastasis in patients with high levels of the PRLR [1]. Understanding the mechanism that accelerates the vicious cycle is key to therapeutic development.
Osteoclasts undergo both differentiation and functional activation as distinct stages and can morphologically differentiate without the ability to degrade bone matrix. Osteoclasts adhere to and migrate on the bone surface, synthesize and secrete hydrolytic enzymes, acidify the bone and internalize some degradation products [44]. To accomplish this, the osteoclast undergoes fusion to form multinucleate cells, cytoskeletal reorganization (actin ring) and polarization to establish a resorptive organelle called the ruffled border, which contacts the bone surface and constitutes the apical membrane. The cell then releases acidic components and lytic enzymes, such as tartrate-resistant acid phosphatase (TRAP). Many molecules act at different key steps in the process, such as macrophage colony stimulating factor (M-CSF), macrophage inflammatory protein-3 α (MIP3α), cardiotrophin-1 (CT-1) (for cell proliferation, survival, cell fusion, differentiation) [45,46,47] and receptor activator of nuclear-factor-κB (NFκB) ligand (RANKL) (for differentiation, survival and function), and other molecules are involved in attachment, actin cytoskeleton remodeling and the acidification process. The factors secreted by breast cancer cells in the presence of PRL stimulate osteoclast differentiation and lytic activity.
Three main pathways are essential for osteoclast differentiation, from the RANKL-RANK receptor, M-CSF-c-Fms and co-stimulatory signals [48,49]. Calcium and RANKL induce NFκB and the master regulator of osteoclastogenesis, nuclear factor of activated T cells-1 (NFATc1) [50], responsible for regulating the genes for TRAP, calcitonin receptor, cathepsin K and β3 integrin [49]. M-CSF upregulates the transcription factor c-fos via ERK [49]. Non-canonical pathways exist in arthritis, whereby RANKL can be substituted by “homologous to lymphotoxins exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes” (LIGHT), tumor necrosis factor α (TNFα), IL-6, IL-11 and IL-8 [51]. Therefore, it is possible that non-RANKL-dependent pathways exist.
Bone metastases is incurable and has limited treatment options. Current treatments include bisphosphonates. Despite treatment, over 50% of patients treated with bisphosphonates will have a recurrence with skeletal-related events [52]. The humanized monoclonal antibody against RANKL (Denosumab) offers improvement over certain bisphosphonates, reduces the risk of bone fracture in breast cancer patients by 50% and delays skeletal-related events [53]. Suboptimal therapy and ineffective anti-RANKL treatments in patient non-responders [54] may be explained by the presence of RANKL-independent pathways. Identification of a RANKL-independent pathway can offer the therapeutic option of co-targeting it and the RANKL pathway.

2.2. Osteoclastogenic Factors Produced by Breast Cancer Cells

Breast cancer cells secrete cytokines, such as parathyroid hormone-related protein (PTHrP) [55], vascular endothelial growth factor (VEGF) [56], interleukin (IL)-6 [57], IL-8 [58] and IL-11 [59] (Figure 1), which are known bone modulators. Breast cancer cells also secrete many others into the metastatic niche, which influence bone metastasis (Table 1). PTHrP is classically a major player, with elevated expression in tumors that have metastasized to the bone as opposed to tumors that have a visceral metastasis [60], although conflicting reports indicate that it is associated with non-bone metastasis and a good prognosis [61]. PTHrP interacts with receptors on osteoblasts that results in an increase in RANKL and decrease in osteoprotegerin (OPG) secretion. As OPG is an inhibitor of RANKL, the increase in the RANKL-OPG ratio favors osteolytic lesions [42]. RANKL is secreted by breast cancer cells in response to progesterone [62,63], although this mechanism has not been directly implicated in osteolysis. VEGF expression is present at high levels in breast cancer metastases to the bone, where it induces mature osteolytic osteoclasts [56,64] and increases their survival [65]. Il-6, IL-8 and IL-11 stimulate osteoclasts directly in addition to osteoblasts and bone stroma at the site of metastasis [66,67,68]. It is clear now that there are multiple breast cancer-secreted factors that can influence the osteolytic metastatic niche (Table 1), in general by usurping the natural production of factors that have multiple cell type-dependent roles.

2.3. Osteoblastic Factors Produced by Breast Cancer Cells

Although breast cancer is primarily osteolytic, the metastatic lesion can also result in a build-up of bone, which is also harmful. In these cases, breast cancer cells likely secrete factors that influence osteoblast function that results in bone build-up as opposed to osteoclast differentiation and bone loss. There are a number of potential factors that are not well understood in breast cancer, which are however better understood in prostate cancer, which is primarily osteoblastic [92]. At least one breast cancer-secreted factor, platelet-derived growth factor (PDGF)-β polypeptide B (BB), has been observed to be osteosclerotic, promoting bone density [93].

3. Prolactin in Bone Homeostasis: Pregnancy and Lactation

There are two main phases of bone changes associated with reproduction, with an increase in bone in early pregnancy and bone loss in later pregnancy and lactation in the mother in order to ultimately provide calcium to the milk. PRL appears to have a role in the late pregnancy and lactation-associated bone loss within the mother [94]. PRL may be responsible for bone loss at lactation [94,95,96], consistent with evidence [97,98,99] that demonstrates a direct effect of PRL on osteoblasts, which express the PRLR. These results are consistent with the phenotype of hyperprolactinemia patients, who experience bone loss [100], thought to be either due to the indirect effect of PRL that results in hypogonadism, and therefore, low estrogen, or alternatively by the direct action of PRL on osteoblasts [99,101]. PRL-PRLR directly increases bone turnover by raising the RANKL/OPG ratio [99,102]. PRL induction of osteoblasts was shown to increase the expression of RANKL, monocyte chemoattractant protein-1 (MCP-1), cyclooxygenase-2 (COX-2), ephrin-B1 (EPHB1), TNFα and IL-1 [101]. Interestingly, in fetal bone cells, PRL appears to promote bone gain in both rat and in human cells [97], resulting in an age-dependent response. In young rats, PRL was also shown to promote calcium absorption [103]. Osteoclasts do not express the PRLR [102], so any effect of PRL on osteoclasts would be indirect, including via PRLR+ osteoblasts or PRLR+ breast cancer cells. PRL can stimulate intestinal calcium and absorption and decreases renal calcium excretion [104]. Overall, PRL is considered to be a major calciotropic hormone that controls calcium mobilization from the bone and absorption in the gut [105].

4. Prolactin and the Regulation of Bone Modulating Factors in the Breast

RANKL was initially implicated as a PRL-STAT5 target gene in the mouse mammary gland, since RANKL expression was decreased in PRLR null mouse models [106], and induced by PRL [107,108]. The mammary gland phenotype of RANKL deletion [107] also resembles that of PRL-PRLR deficiency [3,4], in that there is a failed alveolargenesis and reduced ductal branching. Its pathway became more clear when it was determined that RANKL could rescue the progesterone receptor (PR) knockout mammary phenotype of side branching and alveolargenesis, and RANKL is a mediator of PR-E74-like factor 5 (ETS domain transcription factor) (ELF5)-induced alveolargenesis [109,110]. Recent work indicates that RANKL impairs PRL-STAT5 signaling and that this inhibition must be lifted in order for the functional differentiation of the mammary gland to take place [111]. Therefore, RANKL has two roles at different stage of mammary gland development, one mediating progesterone functions to promote early alveolargenesis and the second to help time lactogenic differentiation.
PTHrP [112], VEGF [113] and M-CSF [114] are upregulated by PRL in the mammary gland (Table 2). PTHrP is essential for calcium transport in the milk [115]. VEGF makes an important contribution to mammary gland function, in particular lobulo-alveolar expansion and milk production [116]. M-CSF is important for the lactating phenotype in the mammary gland and is also present in the milk [117]. It is likely that these well-known bone-modulators in the breast are important for PRL function.
As discussed below, PRL also induces Sonic Hedgehog (SHH) at the protein level in breast cancer cells, although the signal transduction pathway is not known. SHH is produced in the breast although its function is not clearly linked to PRL. In fact, although there is SHH expression in the mammary gland, its function is not clear [118]. Hedgehog (HH) ligands, SHH, Indian HH and Desert HH, are expressed in the postnatal mammary gland. Components of the HH pathway (Figure 2) are required for ductal patterning and elongation [118]. Indian HH contributes to mammary epithelial expansion from stem and progenitor cells during pregnancy [119], consistent with PRL function. SHH is capable of activating non-canonical HH pathways in the mammary gland, such as extracellular regulated kinase (ERK) [120]. Hedgehog signaling, via cilia formation, is important in branching morphogenesis and pregnancy-induced alveolargenesis [121], consistent with indirect and direct PRL function. It will be interesting in the future to understand how these pathways interact.

5. The Role of Prolactin in Breast Cancer-Mediated Osteoclastogenesis

We discovered that PRL can escalate the osteolytic aspect of the vicious cycle, by stimulating pre-osteoclasts indirectly to differentiate into osteolytic cells through breast cancer secreted factors, such as SHH [1] (Figure 3). High PRLR expression in the primary breast tumour was associated with a shorter time to the clinical presentation of bone metastasis. We also detected PRLR expression on circulating tumour cells in peripheral blood and in paired primary breast tumour and bone metastatic samples [1]. PRL and the PRLR enhanced the endogenous capacity of the breast cancer cells to directly induce the differentiation of osteoclasts via production of soluble factors and also contributed to their osteolytic ability. The molecular mechanism, in part, involved the PRL-induced upregulation of SHH at the protein level from breast cancer cells. Breast cancer-secreted SHH is capable of inducing osteoclast differentiation both directly and indirectly via osteoclasts or osteoblasts [88,89]. This is the first PRL-based molecular mechanism that has been established in breast cancer metastases, in particular to breast cancer metastases to the bone.

6. Future Directions and Impact: Therapeutic Implications

PRL signaling is complex, although it is clear that PRL could have an important impact on breast cancer bone metastases. The natural production of factors in the breast that also have roles in the bone is consistent with the cell type-specific control over a limited number of secreted factors in the body. Metastasis of cancer cells results in drastically altered microenvironments that affects multiple cell types and greatly alters normal homeostasis, resulting in an imbalance of osteolytic factors and the production of a lytic bone lesion. What is breast in the bone, in this case, is the PRL-regulated factors (and others) of transformed mammary epithelial cells that have metastasized to the bone, which usurp the normal homeostasis and push the local environment to bone loss. These observations also identify the PRLR as a potential therapeutic target in not only breast cancer, but for breast cancer bone metastases.

Acknowledgments

We thank Heidi Forsyth for her artistic preparation of the figures. We thank the Canadian Breast Cancer Foundation for trainee support.

Author Contributions

Carrie S. Shemanko wrote and coordinated preparation of the manuscript. Yingying Cong made substantial contributions to Table 1 and to the literature review. Amanda Forsyth contributed the first draft of key sections of the manuscript and directed preparation of the figures.

Conflicts of Interest

The authors declare no conflict of interest. The founding sponsors had no role in the design of the study; in the collection, analyses or interpretation of the data; in the writing of the manuscript; nor in the decision to publish the results.

Abbreviations

CT-1cardiotrophin
COX-2cyclooxygenase-2
ELF5E74-like factor 5 (ETS domain transcription factor)
EPHB1ephrin-B1
ERKextracellular regulated kinase
GSK3βglycogen synthase kinase-3β
JAK2Janus kinase-2
HHhedgehog
IGFinsulin-like growth factor
ILinterleukin
LIGHThomologous to lymphotoxins exhibiting inducible expression and competing with herpes simplex virus glycoprotein D for herpesvirus entry mediator (HVEM), a receptor expressed by T lymphocytes
MCP-1monocyte chemoattractant protein-1
M-CSFmacrophage colony stimulating factor
MIP3αmacrophage inflammatory protein-3 α
NFATc1nuclear factor of activated T cells-1
OPGosteoprotegerin
PDGF-BBplatelet-derived growth factor β polypeptide B
PKAprotein kinase-A
PRprogesterone receptor
PRLprolactin
PRLRprolactin receptor
PTCH1patched-1
PTHrPparathyroid hormone-related protein
RANKLreceptor activator of nuclear factor-κB (NFκB) ligand
SMOsmoothened
STAT5asignal transducer and activator of transcription-5a
SUFUsuppressor of fused
TGF-βtransforming growth factor-β
TNFαtumor necrosis factor α
TRAPtartrate-resistant acid phosphatase-1
VEGFvascular endothelial growth factor

References

  1. Sutherland, A.; Forsyth, A.; Cong, Y.; Grant, L.; Juan, T.H.; Lee, J.K.; Klimowicz, A.; Petrillo, S.K.; Hu, J.; Chan, A.; et al. The role of prolactin in bone metastasis and breast cancer cell-mediated osteoclast differentiation. J. Natl. Cancer Inst. 2016, 108, djv338. [Google Scholar] [CrossRef] [PubMed]
  2. Brisken, C.; Kaur, S.; Chavarria, T.E.; Binart, N.; Sutherland, R.L.; Weinberg, R.A.; Kelly, P.A.; Ormandy, C.J. Prolactin controls mammary gland development via direct and indirect mechanisms. Dev. Biol. 1999, 210, 96–106. [Google Scholar] [CrossRef] [PubMed]
  3. Horseman, N.D.; Zhao, W.; Montecino-Rodriguez, E.; Tanaka, M.; Nakashima, K.; Engle, S.J.; Smith, F.; Markoff, E.; Dorshkind, K. Defective mammopoiesis, but normal hematopoiesis, in mice with a targeted disruption of the prolactin gene. EMBO J. 1997, 16, 6926–6935. [Google Scholar] [CrossRef] [PubMed]
  4. Ormandy, C.J.; Camus, A.; Barra, J.; Damotte, D.; Lucas, B.; Buteau, H.; Edery, M.; Brousse, N.; Babinet, C.; Binart, N.; et al. Null mutation of the prolactin receptor gene produces multiple reproductive defects in the mouse. Genes Dev. 1997, 11, 167–178. [Google Scholar] [CrossRef] [PubMed]
  5. Shillingford, J.M.; Miyoshi, K.; Robinson, G.W.; Grimm, S.L.; Rosen, J.M.; Neubauer, H.; Pfeffer, K.; Hennighausen, L. JAK2 is an essential tyrosine kinase involved in pregnancy-mediated development of mammary secretory epithelium. Mol. Endocrinol. 2002, 16, 563–570. [Google Scholar] [CrossRef] [PubMed]
  6. Wagner, K.U.; Krempler, A.; Triplett, A.A.; Qi, Y.; George, N.M.; Zhu, J.; Rui, H. Impaired alveologenesis and maintenance of secretory mammary epithelial cells in JAK2 conditional knockout mice. Mol. Cell. Biol. 2004, 24, 5510–5520. [Google Scholar] [CrossRef] [PubMed]
  7. Cui, Y.; Riedlinger, G.; Miyoshi, K.; Tang, W.; Li, C.; Deng, C.X.; Robinson, G.W.; Hennighausen, L. Inactivation of STAT5 in mouse mammary epithelium during pregnancy reveals distinct functions in cell proliferation, survival, and differentiation. Mol. Cell. Biol. 2004, 24, 8037–8047. [Google Scholar] [CrossRef] [PubMed]
  8. Miyoshi, K.; Shillingford, J.M.; Smith, G.H.; Grimm, S.L.; Wagner, K.U.; Oka, T.; Rosen, J.M.; Robinson, G.W.; Hennighausen, L. Signal transducer and activator of transcription (STAT) 5 controls the proliferation and differentiation of mammary alveolar epithelium. J. Cell Biol. 2001, 155, 531–542. [Google Scholar] [CrossRef] [PubMed]
  9. Yamaji, D.; Na, R.; Feuermann, Y.; Pechhold, S.; Chen, W.; Robinson, G.W.; Hennighausen, L. Development of mammary luminal progenitor cells is controlled by the transcription factor STAT5a. Genes Dev. 2009, 23, 2382–2387. [Google Scholar] [CrossRef] [PubMed]
  10. Rose-Hellekant, T.A.; Arendt, L.M.; Schroeder, M.D.; Gilchrist, K.; Sandgren, E.P.; Schuler, L.A. Prolactin induces eralpha-positive and eralpha-negative mammary cancer in transgenic mice. Oncogene 2003, 22, 4664–4674. [Google Scholar] [CrossRef] [PubMed]
  11. Wennbo, H.; Gebre-Medhin, M.; Gritli-Linde, A.; Ohlsson, C.; Isaksson, O.G.; Tornell, J. Activation of the prolactin receptor but not the growth hormone receptor is important for induction of mammary tumors in transgenic mice. J. Clin. Investig. 1997, 100, 2744–2751. [Google Scholar] [CrossRef] [PubMed]
  12. Tikk, K.; Sookthai, D.; Johnson, T.; Rinaldi, S.; Romieu, I.; Tjonneland, A.; Olsen, A.; Overvad, K.; Clavel-Chapelon, F.; Baglietto, L.; et al. Circulating prolactin and breast cancer risk among pre- and postmenopausal women in the epic cohort. Ann. Oncol. 2014, 25, 1422–1428. [Google Scholar] [CrossRef] [PubMed]
  13. Tworoger, S.S.; Eliassen, A.H.; Zhang, X.; Qian, J.; Sluss, P.M.; Rosner, B.A.; Hankinson, S.E. A 20-year prospective study of plasma prolactin as a risk marker of breast cancer development. Cancer Res. 2013, 73, 4810–4819. [Google Scholar] [CrossRef] [PubMed]
  14. Albrektsen, G.; Heuch, I.; Kvale, G. The short-term and long-term effect of a pregnancy on breast cancer risk: A prospective study of 802,457 parous norwegian women. Br. J. Cancer 1995, 72, 480–484. [Google Scholar] [CrossRef] [PubMed]
  15. Bhatavdekar, J.M.; Patel, D.D.; Shah, N.G.; Vora, H.H.; Suthar, T.P.; Ghosh, N.; Chikhlikar, P.R.; Trivedi, T.I. Prolactin as a local growth promoter in patients with breast cancer: Gcri experience. Eur. J. Surg. Oncol. 2000, 26, 540–547. [Google Scholar] [CrossRef] [PubMed]
  16. Patel, D.D.; Bhatavdekar, J.M.; Chikhlikar, P.R.; Ghosh, N.; Suthar, T.P.; Shah, N.G.; Mehta, R.H.; Balar, D.B. Node negative breast carcinoma: Hyperprolactinemia and/or overexpression of p53 as an independent predictor of poor prognosis compared to newer and established prognosticators. J. Surg. Oncol. 1996, 62, 86–92. [Google Scholar] [CrossRef]
  17. Wang, D.Y.; Stepniewska, K.A.; Allen, D.S.; Fentiman, I.S.; Bulbrook, R.D.; Kwa, H.G.; de Stavola, B.L.; Reed, M.J. Serum prolactin levels and their relationship to survival in women with operable breast cancer. J. Clin. Epidemiol. 1995, 48, 959–968. [Google Scholar] [CrossRef]
  18. Holtkamp, W.; Nagel, G.A.; Wander, H.E.; Rauschecker, H.F.; von Heyden, D. Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. Int. J. Cancer 1984, 34, 323–328. [Google Scholar] [CrossRef] [PubMed]
  19. Bhatavdekar, J.M.; Shah, N.G.; Balar, D.B.; Patel, D.D.; Bhaduri, A.; Trivedi, S.N.; Karelia, N.H.; Ghosh, N.; Shukla, M.K.; Giri, D.D. Plasma prolactin as an indicator of disease progression in advanced breast cancer. Cancer 1990, 65, 2028–2032. [Google Scholar] [CrossRef]
  20. Mujagic, Z.; Mujagic, H. Importance of serum prolactin determination in metastatic breast cancer patients. Croat. Med. J. 2004, 45, 176–180. [Google Scholar] [PubMed]
  21. Bertucci, F.; Nasser, V.; Granjeaud, S.; Eisinger, F.; Adelaide, J.; Tagett, R.; Loriod, B.; Giaconia, A.; Benziane, A.; Devilard, E.; et al. Gene expression profiles of poor-prognosis primary breast cancer correlate with survival. Hum. Mol. Genet. 2002, 11, 863–872. [Google Scholar] [CrossRef] [PubMed]
  22. Waseda, N.; Kato, Y.; Imura, H.; Kurata, M. Prognostic value of estrogen and prolactin receptor analysis in human breast cancer. Jpn. J. Cancer Res. 1985, 76, 517–523. [Google Scholar] [PubMed]
  23. Miller, S.L.; Antico, G.; Raghunath, P.N.; Tomaszewski, J.E.; Clevenger, C.V. Nek3 kinase regulates prolactin-mediated cytoskeletal reorganization and motility of breast cancer cells. Oncogene 2007, 26, 4668–4678. [Google Scholar] [CrossRef] [PubMed]
  24. Nouhi, Z.; Chughtai, N.; Hartley, S.; Cocolakis, E.; Lebrun, J.J.; Ali, S. Defining the role of prolactin as an invasion suppressor hormone in breast cancer cells. Cancer Res. 2006, 66, 1824–1832. [Google Scholar] [CrossRef] [PubMed]
  25. Sultan, A.S.; Xie, J.; LeBaron, M.J.; Ealley, E.L.; Nevalainen, M.T.; Rui, H. STAT5 promotes homotypic adhesion and inhibits invasive characteristics of human breast cancer cells. Oncogene 2005, 24, 746–760. [Google Scholar] [CrossRef] [PubMed]
  26. Sato, T.; Tran, T.H.; Peck, A.R.; Liu, C.; Ertel, A.; Lin, J.; Neilson, L.M.; Rui, H. Global profiling of prolactin-modulated transcripts in breast cancer in vivo. Mol. Cancer 2013, 12, 59. [Google Scholar] [CrossRef] [PubMed]
  27. Hachim, I.Y.; Hachim, M.Y.; Lopez, V.M.; Lebrun, J.J.; Ali, S. Prolactin receptor expression is an independent favorable prognostic marker in human breast cancer. Appl. Immunohistochem. Mol. Morphol. 2016, 24, 238–245. [Google Scholar] [CrossRef] [PubMed]
  28. Hachim, I.Y.; Shams, A.; Lebrun, J.J.; Ali, S. A favorable role of prolactin in human breast cancer reveals novel pathway based gene signatures indicative of tumor differentiation and favorable patient outcome: Prolactin-induced mammary differentiation program in breast cancer prognosis. Hum. Pathol. 2016, 53, 142–152. [Google Scholar] [CrossRef] [PubMed]
  29. Shemanko, C.S. Prolactin receptor in breast cancer: Marker for metastatic risk. J. Mol. Endocrinol. 2016, 57, R153–R165. [Google Scholar] [CrossRef] [PubMed]
  30. Barcus, C.E.; Holt, E.C.; Keely, P.J.; Eliceiri, K.W.; Schuler, L.A. Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells. PLoS ONE 2015, 10, e0116891. [Google Scholar] [CrossRef] [PubMed]
  31. Barcus, C.E.; Keely, P.J.; Eliceiri, K.W.; Schuler, L.A. Stiff collagen matrices increase tumorigenic prolactin signaling in breast cancer cells. J. Biol. Chem. 2013, 288, 12722–12732. [Google Scholar] [CrossRef] [PubMed]
  32. Barcus, C.E.; Keely, P.J.; Eliceiri, K.W.; Schuler, L.A. Prolactin signaling through focal adhesion complexes is amplified by stiff extracellular matrices in breast cancer cells. Oncotarget 2016, 7, 48093–48106. [Google Scholar] [CrossRef] [PubMed]
  33. Ginsburg, E.; Vonderhaar, B.K. Prolactin synthesis and secretion by human breast cancer cells. Cancer Res. 1995, 55, 2591–2595. [Google Scholar] [PubMed]
  34. Clevenger, C.V. Role of prolactin/prolactin receptor signaling in human breast cancer. Breast Dis. 2003, 18, 75–86. [Google Scholar] [CrossRef] [PubMed]
  35. Ferrag, F.; Chiarenza, A.; Goffin, V.; Kelly, P.A. Convergence of signaling transduced by prolactin (PRL)/cytokine chimeric receptors on PRL-responsive gene transcription. Mol. Endocrinol. 1996, 10, 451–460. [Google Scholar] [CrossRef] [PubMed]
  36. Ferrag, F.; Goffin, V.; Buteau, H.; Kelly, P.A. Immune function of prolactin (PRL) and signal transduction by PRL/GH/cytokine receptors: Specificity, redundancy and lessons from chimaeras. Cytokines Cell. Mol. Ther. 1997, 3, 197–213. [Google Scholar] [PubMed]
  37. Courtillot, C.; Chakhtoura, Z.; Bogorad, R.; Genestie, C.; Bernichtein, S.; Badachi, Y.; Janaud, G.; Akakpo, J.P.; Bachelot, A.; Kuttenn, F.; et al. Characterization of two constitutively active prolactin receptor variants in a cohort of 95 women with multiple breast fibroadenomas. J. Clin. Endocrinol. Metab. 2010, 95, 271–279. [Google Scholar] [CrossRef] [PubMed]
  38. Chakhtoura, Z.; Laki, F.; Bernadet, M.; Cherifi, I.; Chiche, A.; Pigat, N.; Bernichtein, S.; Courtillot, C.; Boutillon, F.; Bieche, I.; et al. Gain-of-function prolactin receptor variants are not associated with breast cancer and multiple fibroadenoma risk. J. Clin. Endocrinol. Metab. 2016. [Google Scholar] [CrossRef] [PubMed]
  39. Chen, Y.C.; Sosnoski, D.M.; Mastro, A.M. Breast cancer metastasis to the bone: Mechanisms of bone loss. Breast Cancer Res. 2010, 12, 215. [Google Scholar] [CrossRef] [PubMed]
  40. Lipton, A.; Uzzo, R.; Amato, R.J.; Ellis, G.K.; Hakimian, B.; Roodman, G.D.; Smith, M.R. The science and practice of bone health in oncology: Managing bone loss and metastasis in patients with solid tumors. J. Natl. Compr. Cancer Netw. 2009, 7 (Suppl. S7), S1–S29. [Google Scholar]
  41. Akhtari, M.; Mansuri, J.; Newman, K.A.; Guise, T.M.; Seth, P. Biology of breast cancer bone metastasis. Cancer Biol. Ther. 2008, 7, 3–9. [Google Scholar] [CrossRef] [PubMed]
  42. Mundy, G.R. Metastasis to bone: Causes, consequences and therapeutic opportunities. Nat. Rev. Cancer 2002, 2, 584–593. [Google Scholar] [CrossRef] [PubMed]
  43. Kingsley, L.A.; Fournier, P.G.; Chirgwin, J.M.; Guise, T.A. Molecular biology of bone metastasis. Mol. Cancer Ther. 2007, 6, 2609–2617. [Google Scholar] [CrossRef] [PubMed]
  44. Bruzzaniti, A.; Baron, R. Molecular regulation of osteoclast activity. Rev. Endocr. Metab. Disord. 2006, 7, 123–139. [Google Scholar] [CrossRef] [PubMed]
  45. Lisignoli, G.; Piacentini, A.; Cristino, S.; Grassi, F.; Cavallo, C.; Cattini, L.; Tonnarelli, B.; Manferdini, C.; Facchini, A. CCL20 chemokine induces both osteoblast proliferation and osteoclast differentiation: Increased levels of CCL20 are expressed in subchondral bone tissue of rheumatoid arthritis patients. J. Cell. Physiol. 2007, 210, 798–806. [Google Scholar] [CrossRef] [PubMed]
  46. Nakao, K.; Aoyama, M.; Fukuoka, H.; Fujita, M.; Miyazawa, K.; Asai, K.; Goto, S. IGF2 modulates the microenvironment for osteoclastogenesis. Biochem. Biophys. Res. Commun. 2009, 378, 462–466. [Google Scholar] [CrossRef] [PubMed]
  47. Walker, E.C.; McGregor, N.E.; Poulton, I.J.; Pompolo, S.; Allan, E.H.; Quinn, J.M.; Gillespie, M.T.; Martin, T.J.; Sims, N.A. Cardiotrophin-1 is an osteoclast-derived stimulus of bone formation required for normal bone remodeling. J. Bone Miner. Res. 2008, 23, 2025–2032. [Google Scholar] [CrossRef] [PubMed]
  48. Koga, T.; Inui, M.; Inoue, K.; Kim, S.; Suematsu, A.; Kobayashi, E.; Iwata, T.; Ohnishi, H.; Matozaki, T.; Kodama, T.; et al. Costimulatory signals mediated by the itam motif cooperate with RANKL for bone homeostasis. Nature 2004, 428, 758–763. [Google Scholar] [CrossRef] [PubMed]
  49. Negishi-Koga, T.; Takayanagi, H. Ca2+-NFATc1 signaling is an essential axis of osteoclast differentiation. Immunol. Rev. 2009, 231, 241–256. [Google Scholar] [CrossRef] [PubMed]
  50. Takayanagi, H. Mechanistic insight into osteoclast differentiation in osteoimmunology. J. Mol. Med. 2005, 83, 170–179. [Google Scholar] [CrossRef] [PubMed]
  51. Knowles, H.J.; Athanasou, N.A. Canonical and non-canonical pathways of osteoclast formation. Histol. Histopathol. 2009, 24, 337–346. [Google Scholar] [PubMed]
  52. Powles, T.; Paterson, A.; McCloskey, E.; Schein, P.; Scheffler, B.; Tidy, A.; Ashley, S.; Smith, I.; Ottestad, L.; Kanis, J. Reduction in bone relapse and improved survival with oral clodronate for adjuvant treatment of operable breast cancer [ISRCTN83688026]. Breast Cancer Res. 2006, 8, R13. [Google Scholar] [CrossRef] [PubMed]
  53. Gul, G.; Sendur, M.A.; Aksoy, S.; Sever, A.R.; Altundag, K. A comprehensive review of denosumab for bone metastasis in patients with solid tumors. Curr. Med. Res. Opin. 2016, 32, 133–145. [Google Scholar] [CrossRef] [PubMed]
  54. Goessl, C.; Katz, L.; Dougall, W.C.; Kostenuik, P.J.; Zoog, H.B.; Braun, A.; Dansey, R.; Wagman, R.B. The development of denosumab for the treatment of diseases of bone loss and cancer-induced bone destruction. Ann. N. Y. Acad. Sci. 2012, 1263, 29–40. [Google Scholar] [CrossRef] [PubMed]
  55. Guise, T.A.; Yin, J.J.; Taylor, S.D.; Kumagai, Y.; Dallas, M.; Boyce, B.F.; Yoneda, T.; Mundy, G.R. Evidence for a causal role of parathyroid hormone-related protein in the pathogenesis of human breast cancer-mediated osteolysis. J. Clin. Investig. 1996, 98, 1544–1549. [Google Scholar] [CrossRef] [PubMed]
  56. Aldridge, S.E.; Lennard, T.W.; Williams, J.R.; Birch, M.A. Vascular endothelial growth factor receptors in osteoclast differentiation and function. Biochem. Biophys. Res. Commun. 2005, 335, 793–798. [Google Scholar] [CrossRef] [PubMed]
  57. Suarez-Cuervo, C.; Harris, K.W.; Kallman, L.; Vaananen, H.K.; Selander, K.S. Tumor necrosis factor-α induces interleukin-6 production via extracellular-regulated kinase 1 activation in breast cancer cells. Breast Cancer Res. Treat. 2003, 80, 71–78. [Google Scholar] [CrossRef] [PubMed]
  58. Bendre, M.S.; Montague, D.C.; Peery, T.; Akel, N.S.; Gaddy, D.; Suva, L.J. Interleukin-8 stimulation of osteoclastogenesis and bone resorption is a mechanism for the increased osteolysis of metastatic bone disease. Bone 2003, 33, 28–37. [Google Scholar] [CrossRef]
  59. McCoy, E.M.; Hong, H.; Pruitt, H.C.; Feng, X. IL-11 produced by breast cancer cells augments osteoclastogenesis by sustaining the pool of osteoclast progenitor cells. BMC Cancer 2013, 13, 16. [Google Scholar] [CrossRef] [PubMed]
  60. Powell, G.J.; Southby, J.; Danks, J.A.; Stillwell, R.G.; Hayman, J.A.; Henderson, M.A.; Bennett, R.C.; Martin, T.J. Localization of parathyroid hormone-related protein in breast cancer metastases: Increased incidence in bone compared with other sites. Cancer Res. 1991, 51, 3059–3061. [Google Scholar] [PubMed]
  61. Henderson, M.; Danks, J.; Moseley, J.; Slavin, J.; Harris, T.; McKinlay, M.; Hopper, J.; Martin, T. Parathyroid hormone-related protein production by breast cancers, improved survival, and reduced bone metastases. J. Natl. Cancer Inst. 2001, 93, 234–237. [Google Scholar] [CrossRef] [PubMed]
  62. Gonzalez-Suarez, E.; Jacob, A.P.; Jones, J.; Miller, R.; Roudier-Meyer, M.P.; Erwert, R.; Pinkas, J.; Branstetter, D.; Dougall, W.C. Rank ligand mediates progestin-induced mammary epithelial proliferation and carcinogenesis. Nature 2010, 468, 103–107. [Google Scholar] [CrossRef] [PubMed]
  63. Schramek, D.; Leibbrandt, A.; Sigl, V.; Kenner, L.; Pospisilik, J.A.; Lee, H.J.; Hanada, R.; Joshi, P.A.; Aliprantis, A.; Glimcher, L.; et al. Osteoclast differentiation factor rankl controls development of progestin-driven mammary cancer. Nature 2010, 468, 98–102. [Google Scholar] [CrossRef] [PubMed]
  64. Aldridge, S.E.; Lennard, T.W.; Williams, J.R.; Birch, M.A. Vascular endothelial growth factor acts as an osteolytic factor in breast cancer metastases to bone. Br. J. Cancer 2005, 92, 1531–1537. [Google Scholar] [CrossRef] [PubMed]
  65. Nakagawa, M.; Kaneda, T.; Arakawa, T.; Morita, S.; Sato, T.; Yomada, T.; Hanada, K.; Kumegawa, M.; Hakeda, Y. Vascular endothelial growth factor (VEGF) directly enhances osteoclastic bone resorption and survival of mature osteoclasts. FEBS Lett. 2000, 473, 161–164. [Google Scholar] [CrossRef]
  66. Fontanini, G.; Campani, D.; Roncella, M.; Cecchetti, D.; Calvo, S.; Toniolo, A.; Basolo, F. Expression of interleukin 6 (IL-6) correlates with oestrogen receptor in human breast carcinoma. Br. J. Cancer 1999, 80, 579–584. [Google Scholar] [CrossRef] [PubMed]
  67. Kurebayashi, J. Regulation of interleukin-6 secretion from breast cancer cells and its clinical implications. Breast Cancer 2000, 7, 124–129. [Google Scholar] [CrossRef] [PubMed]
  68. Manolagas, S.C. Role of cytokines in bone resorption. Bone 1995, 17, 63S–67S. [Google Scholar] [CrossRef]
  69. Hernandez, L.L.; Gregerson, K.A.; Horseman, N.D. Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals. Am. J. Physiol. Endocrinol. Metab. 2012, 302, E1009–E1015. [Google Scholar] [CrossRef] [PubMed]
  70. Lu, X.; Wang, Q.; Hu, G.; Van Poznak, C.; Fleisher, M.; Reiss, M.; Massague, J.; Kang, Y. Adamts1 and mmp1 proteolytically engage egf-like ligands in an osteolytic signaling cascade for bone metastasis. Genes Dev. 2009, 23, 1882–1894. [Google Scholar] [CrossRef] [PubMed]
  71. Lu, X.; Kang, Y. Chemokine (C–C motif) ligand 2 engages CCR2+ stromal cells of monocytic origin to promote breast cancer metastasis to lung and bone. J. Biol. Chem. 2009, 284, 29087–29096. [Google Scholar] [CrossRef] [PubMed]
  72. Ouellet, V.; Tiedemann, K.; Mourskaia, A.; Fong, J.E.; Tran-Thanh, D.; Amir, E.; Clemons, M.; Perbal, B.; Komarova, S.V.; Siegel, P.M. CCN3 impairs osteoblast and stimulates osteoclast differentiation to favor breast cancer metastasis to bone. Am. J. Pathol. 2011, 178, 2377–2388. [Google Scholar] [CrossRef] [PubMed]
  73. Kang, Y.; Siegel, P.M.; Shu, W.; Drobnjak, M.; Kakonen, S.M.; Cordon-Cardo, C.; Guise, T.A.; Massague, J. A multigenic program mediating breast cancer metastasis to bone. Cancer Cell 2003, 3, 537–549. [Google Scholar] [CrossRef]
  74. Voorzanger-Rousselot, N.; Goehrig, D.; Journe, F.; Doriath, V.; Body, J.J.; Clezardin, P.; Garnero, P. Increased dickkopf-1 expression in breast cancer bone metastases. Br. J. Cancer 2007, 97, 964–970. [Google Scholar] [CrossRef] [PubMed]
  75. Mancino, A.T.; Klimberg, V.S.; Yamamoto, M.; Manolagas, S.C.; Abe, E. Breast cancer increases osteoclastogenesis by secreting M-CSF and upregulating RANKL in stromal cells. J. Surg. Res. 2001, 100, 18–24. [Google Scholar] [CrossRef] [PubMed]
  76. Park, B.K.; Zhang, H.; Zeng, Q.; Dai, J.; Keller, E.T.; Giordano, T.; Gu, K.; Shah, V.; Pei, L.; Zarbo, R.J.; et al. NF-κB in breast cancer cells promotes osteolytic bone metastasis by inducing osteoclastogenesis via GM-CSF. Nat. Med. 2007, 13, 62–69. [Google Scholar] [CrossRef] [PubMed]
  77. Logan, J.G.; Sophocleous, A.; Marino, S.; Muir, M.; Brunton, V.G.; Idris, A.I. Selective tyrosine kinase inhibition of insulin-like growth factor-1 receptor inhibits human and mouse breast cancer-induced bone cell activity, bone remodeling, and osteolysis. J. Bone Miner. Res. 2013, 28, 1229–1242. [Google Scholar] [CrossRef] [PubMed]
  78. Bendre, M.S.; Margulies, A.G.; Walser, B.; Akel, N.S.; Bhattacharrya, S.; Skinner, R.A.; Swain, F.; Ramani, V.; Mohammad, K.S.; Wessner, L.L.; et al. Tumor-derived interleukin-8 stimulates osteolysis independent of the receptor activator of nuclear factor-κB ligand pathway. Cancer Res. 2005, 65, 11001–11009. [Google Scholar] [CrossRef] [PubMed]
  79. Sotiriou, C.; Lacroix, M.; Lespagnard, L.; Larsimont, D.; Paesmans, M.; Body, J.J. Interleukins-6 and -11 expression in primary breast cancer and subsequent development of bone metastases. Cancer Lett. 2001, 169, 87–95. [Google Scholar] [CrossRef]
  80. Sethi, N.; Dai, X.; Winter, C.G.; Kang, Y. Tumor-derived jagged1 promotes osteolytic bone metastasis of breast cancer by engaging notch signaling in bone cells. Cancer Cell 2011, 19, 192–205. [Google Scholar] [CrossRef] [PubMed]
  81. Eck, S.M.; Hoopes, P.J.; Petrella, B.L.; Coon, C.I.; Brinckerhoff, C.E. Matrix metalloproteinase-1 promotes breast cancer angiogenesis and osteolysis in a novel in vivo model. Breast Cancer Res. Treat. 2009, 116, 79–90. [Google Scholar] [CrossRef] [PubMed]
  82. Suarez-Cuervo, C.; Merrell, M.A.; Watson, L.; Harris, K.W.; Rosenthal, E.L.; Vaananen, H.K.; Selander, K.S. Breast cancer cells with inhibition of p38α have decreased MMP-9 activity and exhibit decreased bone metastasis in mice. Clin. Exp. Metastasis 2004, 21, 525–533. [Google Scholar] [CrossRef] [PubMed]
  83. Bolin, C.; Tawara, K.; Sutherland, C.; Redshaw, J.; Aranda, P.; Moselhy, J.; Anderson, R.; Jorcyk, C.L. Oncostatin m promotes mammary tumor metastasis to bone and osteolytic bone degradation. Genes Cancer 2012, 3, 117–130. [Google Scholar] [CrossRef] [PubMed]
  84. Garrett, I.R.; Boyce, B.F.; Oreffo, R.O.; Bonewald, L.; Poser, J.; Mundy, G.R. Oxygen-derived free radicals stimulate osteoclastic bone resorption in rodent bone in vitro and in vivo. J. Clin. Investig. 1990, 85, 632–639. [Google Scholar] [CrossRef] [PubMed]
  85. Lev, D.C.; Kim, S.J.; Onn, A.; Stone, V.; Nam, D.H.; Yazici, S.; Fidler, I.J.; Price, J.E. Inhibition of platelet-derived growth factor receptor signaling restricts the growth of human breast cancer in the bone of nude mice. Clin. Cancer Res. 2005, 11, 306–314. [Google Scholar] [PubMed]
  86. Rafiei, S.; Tiedemann, K.; Tabaries, S.; Siegel, P.M.; Komarova, S.V. Peroxiredoxin 4: A novel secreted mediator of cancer induced osteoclastogenesis. Cancer Lett. 2015, 361, 262–270. [Google Scholar] [CrossRef] [PubMed]
  87. Yang, Y.H.; Buhamrah, A.; Schneider, A.; Lin, Y.L.; Zhou, H.; Bugshan, A.; Basile, J.R. Semaphorin 4d promotes skeletal metastasis in breast cancer. PLoS ONE 2016, 11, e0150151. [Google Scholar] [CrossRef] [PubMed]
  88. Das, S.; Tucker, J.A.; Khullar, S.; Samant, R.S.; Shevde, L.A. Hedgehog signaling in tumor cells facilitates osteoblast-enhanced osteolytic metastases. PLoS ONE 2012, 7, e34374. [Google Scholar] [CrossRef] [PubMed]
  89. Das, S.; Samant, R.S.; Shevde, L.A. Hedgehog signaling induced by breast cancer cells promotes osteoclastogenesis and osteolysis. J. Biol. Chem. 2011, 286, 9612–9622. [Google Scholar] [CrossRef] [PubMed]
  90. Futakuchi, M.; Nannuru, K.C.; Varney, M.L.; Sadanandam, A.; Nakao, K.; Asai, K.; Shirai, T.; Sato, S.Y.; Singh, R.K. Transforming growth factor-beta signaling at the tumor-bone interface promotes mammary tumor growth and osteoclast activation. Cancer Sci. 2009, 100, 71–81. [Google Scholar] [CrossRef] [PubMed]
  91. Lu, X.; Mu, E.; Wei, Y.; Riethdorf, S.; Yang, Q.; Yuan, M.; Yan, J.; Hua, Y.; Tiede, B.J.; Lu, X.; et al. Vcam-1 promotes osteolytic expansion of indolent bone micrometastasis of breast cancer by engaging α4β1-positive osteoclast progenitors. Cancer Cell 2011, 20, 701–714. [Google Scholar] [CrossRef] [PubMed]
  92. Guise, T.A.; Kozlow, W.M.; Heras-Herzig, A.; Padalecki, S.S.; Yin, J.J.; Chirgwin, J.M. Molecular mechanisms of breast cancer metastases to bone. Clin. Breast Cancer 2005, 5 (Suppl. S2), S46–S53. [Google Scholar] [CrossRef] [PubMed]
  93. Yi, B.; Williams, P.J.; Niewolna, M.; Wang, Y.; Yoneda, T. Tumor-derived platelet-derived growth factor-BB plays a critical role in osteosclerotic bone metastasis in an animal model of human breast cancer. Cancer Res. 2002, 62, 917–923. [Google Scholar] [PubMed]
  94. Suntornsaratoon, P.; Wongdee, K.; Goswami, S.; Krishnamra, N.; Charoenphandhu, N. Bone modeling in bromocriptine-treated pregnant and lactating rats: Possible osteoregulatory role of prolactin in lactation. Am. J. Physiol. Endocrinol. Metab. 2010, 299, E426–E436. [Google Scholar] [CrossRef] [PubMed]
  95. Kovacs, C.S. Calcium and bone metabolism during pregnancy and lactation. J. Mammary Gland Biol. Neoplasia 2005, 10, 105–118. [Google Scholar] [CrossRef] [PubMed]
  96. Kovacs, C.S. Calcium and bone metabolism disorders during pregnancy and lactation. Endocrinol. Metab. Clin. N. Am. 2011, 40, 795–826. [Google Scholar] [CrossRef] [PubMed]
  97. Seriwatanachai, D.; Charoenphandhu, N.; Suthiphongchai, T.; Krishnamra, N. Prolactin decreases the expression ratio of receptor activator of nuclear factor κB ligand/osteoprotegerin in human fetal osteoblast cells. Cell Biol. Int. 2008, 32, 1126–1135. [Google Scholar] [CrossRef] [PubMed]
  98. Seriwatanachai, D.; Krishnamra, N.; van Leeuwen, J.P. Evidence for direct effects of prolactin on human osteoblasts: Inhibition of cell growth and mineralization. J. Cell. Biochem. 2009, 107, 677–685. [Google Scholar] [CrossRef] [PubMed]
  99. Seriwatanachai, D.; Thongchote, K.; Charoenphandhu, N.; Pandaranandaka, J.; Tudpor, K.; Teerapornpuntakit, J.; Suthiphongchai, T.; Krishnamra, N. Prolactin directly enhances bone turnover by raising osteoblast-expressed receptor activator of nuclear factor κB ligand/osteoprotegerin ratio. Bone 2008, 42, 535–546. [Google Scholar] [CrossRef] [PubMed]
  100. Zaidi, M.; Sun, L.; Liu, P.; Davies, T.F.; New, M.; Zallone, A.; Yuen, T. Pituitary-bone connection in skeletal regulation. Horm. Mol. Biol. Clin. Investig. 2016. [Google Scholar] [CrossRef] [PubMed]
  101. Wongdee, K.; Tulalamba, W.; Thongbunchoo, J.; Krishnamra, N.; Charoenphandhu, N. Prolactin alters the mRNA expression of osteoblast-derived osteoclastogenic factors in osteoblast-like UMR106 cells. Mol. Cell. Biochem. 2011, 349, 195–204. [Google Scholar] [CrossRef] [PubMed]
  102. Clement-Lacroix, P.; Ormandy, C.; Lepescheux, L.; Ammann, P.; Damotte, D.; Goffin, V.; Bouchard, B.; Amling, M.; Gaillard-Kelly, M.; Binart, N.; et al. Osteoblasts are a new target for prolactin: Analysis of bone formation in prolactin receptor knockout mice. Endocrinology 1999, 140, 96–105. [Google Scholar] [CrossRef] [PubMed]
  103. Piyabhan, P.; Krishnamra, N.; Limlomwongse, L. Changes in the regulation of calcium metabolism and bone calcium content during growth in the absence of endogenous prolactin and during hyperprolactinemia: A longitudinal study in male and female wistar rats. Can. J. Physiol. Pharmacol. 2000, 78, 757–765. [Google Scholar] [CrossRef] [PubMed]
  104. Wongdee, K.; Charoenphandhu, N. Regulation of epithelial calcium transport by prolactin: From fish to mammals. Gen. Comp. Endocrinol. 2013, 181, 235–240. [Google Scholar] [CrossRef] [PubMed]
  105. Charoenphandhu, N.; Wongdee, K.; Krishnamra, N. Is prolactin the cardinal calciotropic maternal hormone? Trends Endocrinol. Metab. 2010, 21, 395–401. [Google Scholar] [CrossRef] [PubMed]
  106. Ormandy, C.J.; Naylor, M.; Harris, J.; Robertson, F.; Horseman, N.D.; Lindeman, G.J.; Visvader, J.; Kelly, P.A. Investigation of the transcriptional changes underlying functional defects in the mammary glands of prolactin receptor knockout mice. Recent Prog. Horm. Res. 2003, 58, 297–323. [Google Scholar] [CrossRef] [PubMed]
  107. Fata, J.E.; Kong, Y.Y.; Li, J.; Sasaki, T.; Irie-Sasaki, J.; Moorehead, R.A.; Elliott, R.; Scully, S.; Voura, E.B.; Lacey, D.L.; et al. The osteoclast differentiation factor osteoprotegerin-ligand is essential for mammary gland development. Cell 2000, 103, 41–50. [Google Scholar] [CrossRef]
  108. Srivastava, S.; Matsuda, M.; Hou, Z.; Bailey, J.P.; Kitazawa, R.; Herbst, M.P.; Horseman, N.D. Receptor activator of NF-κB ligand induction via JAK2 and STAT5a in mammary epithelial cells. J. Biol. Chem. 2003, 278, 46171–46178. [Google Scholar] [CrossRef] [PubMed]
  109. Mukherjee, A.; Soyal, S.M.; Li, J.; Ying, Y.; He, B.; DeMayo, F.J.; Lydon, J.P. Targeting RANKL to a specific subset of murine mammary epithelial cells induces ordered branching morphogenesis and alveologenesis in the absence of progesterone receptor expression. FASEB J. 2010, 24, 4408–4419. [Google Scholar] [CrossRef] [PubMed]
  110. Lee, H.J.; Gallego-Ortega, D.; Ledger, A.; Schramek, D.; Joshi, P.; Szwarc, M.M.; Cho, C.; Lydon, J.P.; Khokha, R.; Penninger, J.M.; et al. Progesterone drives mammary secretory differentiation via RANKL-mediated induction of Elf5 in luminal progenitor cells. Development 2013, 140, 1397–1401. [Google Scholar] [CrossRef] [PubMed]
  111. Cordero, A.; Pellegrini, P.; Sanz-Moreno, A.; Trinidad, E.M.; Serra-Musach, J.; Deshpande, C.; Dougall, W.C.; Pujana, M.A.; Gonzalez-Suarez, E. RANKL impairs lactogenic differentiation through inhibition of the prolactin/STAT5 pathway at midgestation. Stem Cells 2016, 34, 1027–1039. [Google Scholar] [CrossRef] [PubMed]
  112. Thiede, M.A. The mrna encoding a parathyroid hormone-like peptide is produced in mammary tissue in response to elevations in serum prolactin. Mol. Endocrinol. 1989, 3, 1443–1447. [Google Scholar] [CrossRef] [PubMed]
  113. Goldhar, A.S.; Vonderhaar, B.K.; Trott, J.F.; Hovey, R.C. Prolactin-induced expression of vascular endothelial growth factor via egr-1. Mol. Cell. Endocrinol. 2005, 232, 9–19. [Google Scholar] [CrossRef] [PubMed]
  114. Sapi, E.; Flick, M.B.; Rodov, S.; Carter, D.; Kacinski, B.M. Expression of CSF-I and CSF-I receptor by normal lactating mammary epithelial cells. J. Soc. Gynecol. Investig. 1998, 5, 94–101. [Google Scholar] [CrossRef]
  115. VanHouten, J.; Dann, P.; McGeoch, G.; Brown, E.M.; Krapcho, K.; Neville, M.; Wysolmerski, J.J. The calcium-sensing receptor regulates mammary gland parathyroid hormone-related protein production and calcium transport. J. Clin. Investig. 2004, 113, 598–608. [Google Scholar] [CrossRef] [PubMed]
  116. Rossiter, H.; Barresi, C.; Ghannadan, M.; Gruber, F.; Mildner, M.; Fodinger, D.; Tschachler, E. Inactivation of VEGF in mammary gland epithelium severely compromises mammary gland development and function. FASEB J. 2007, 21, 3994–4004. [Google Scholar] [CrossRef] [PubMed]
  117. Sapi, E. The role of csf-1 in normal physiology of mammary gland and breast cancer: An update. Exp. Biol. Med. 2004, 229, 1–11. [Google Scholar]
  118. Hui, M.; Cazet, A.; Nair, R.; Watkins, D.N.; O'Toole, S.A.; Swarbrick, A. The hedgehog signalling pathway in breast development, carcinogenesis and cancer therapy. Breast Cancer Res. 2013, 15, 203. [Google Scholar] [CrossRef] [PubMed]
  119. Li, N.; Singh, S.; Cherukuri, P.; Li, H.; Yuan, Z.; Ellisen, L.W.; Wang, B.; Robbins, D.; DiRenzo, J. Reciprocal intraepithelial interactions between TP63 and hedgehog signaling regulate quiescence and activation of progenitor elaboration by mammary stem cells. Stem Cells 2008, 26, 1253–1264. [Google Scholar] [CrossRef] [PubMed]
  120. Chang, H.; Li, Q.; Moraes, R.C.; Lewis, M.T.; Hamel, P.A. Activation of erk by sonic hedgehog independent of canonical hedgehog signalling. Int. J. Biochem. Cell Biol. 2010, 42, 1462–1471. [Google Scholar] [CrossRef] [PubMed]
  121. McDermott, K.M.; Liu, B.Y.; Tlsty, T.D.; Pazour, G.J. Primary cilia regulate branching morphogenesis during mammary gland development. Curr. Biol. 2010, 20, 731–737. [Google Scholar] [CrossRef] [PubMed]
Ijms 17 01764 g001 550
Figure 1. The vicious cycle of breast cancer bone metastases. Breast cancer cells secrete soluble factors, including parathyroid hormone-related protein (PTHrP), vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8 and IL-11, which in the bone metastatic site act on osteoblasts and/or osteoclasts. The production of receptor activator of nuclear factor-κB ligand (RANKL), an osteoclast differentiation factor, is increased and the production of osteoprotegerin (OPG) is decreased from osteoblasts. Late-stage pre-osteoclast cells respond to specific breast cancer-secreted factors by differentiation and osteolytic activation.
Figure 1. The vicious cycle of breast cancer bone metastases. Breast cancer cells secrete soluble factors, including parathyroid hormone-related protein (PTHrP), vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8 and IL-11, which in the bone metastatic site act on osteoblasts and/or osteoclasts. The production of receptor activator of nuclear factor-κB ligand (RANKL), an osteoclast differentiation factor, is increased and the production of osteoprotegerin (OPG) is decreased from osteoblasts. Late-stage pre-osteoclast cells respond to specific breast cancer-secreted factors by differentiation and osteolytic activation.
Ijms 17 01764 g001
Ijms 17 01764 g002 550
Figure 2. Hedgehog signaling. In the absence of Hedgehog (HH) ligand, the receptor Patched-1 (PTCH1) indirectly inhibits smoothened (SMO), resulting in the prevention of downstream signaling. Protein kinase-A (PKA) and glycogen synthase kinase β (GSK3β) phosphorylate GLI2/3 to help generate repressor GLI transcription factors (GLI R). Suppressor of fused (SUFU) and Iguana inhibit any activator GLI transcription factors (GLI A). Upon binding of the Sonic Hedgehog (SHH), Indian HH or Desert HH ligands, PTCH1 releases the inhibition of SMO (red X on the inhibitory line), and causes an accumulation of the activator GLI transcription factors and activation of HH target genes.
Figure 2. Hedgehog signaling. In the absence of Hedgehog (HH) ligand, the receptor Patched-1 (PTCH1) indirectly inhibits smoothened (SMO), resulting in the prevention of downstream signaling. Protein kinase-A (PKA) and glycogen synthase kinase β (GSK3β) phosphorylate GLI2/3 to help generate repressor GLI transcription factors (GLI R). Suppressor of fused (SUFU) and Iguana inhibit any activator GLI transcription factors (GLI A). Upon binding of the Sonic Hedgehog (SHH), Indian HH or Desert HH ligands, PTCH1 releases the inhibition of SMO (red X on the inhibitory line), and causes an accumulation of the activator GLI transcription factors and activation of HH target genes.
Ijms 17 01764 g002
Ijms 17 01764 g003 550
Figure 3. Prolactin (PRL)-stimulated breast cancer cells secrete SHH to induce the differentiation of lytic osteoclasts. High levels of the PRL-receptor (PRLR) in the primary tumor are associated with a shorter time to bone metastasis, presumably due to an acceleration of the vicious cycle.
Figure 3. Prolactin (PRL)-stimulated breast cancer cells secrete SHH to induce the differentiation of lytic osteoclasts. High levels of the PRL-receptor (PRLR) in the primary tumor are associated with a shorter time to bone metastasis, presumably due to an acceleration of the vicious cycle.
Ijms 17 01764 g003
Table
Table 1. Breast cancer-secreted factors that induce differentiated osteoclasts indirectly or directly. Factors may act on osteoblasts to indirectly induce osteoclast differentiation or directly on osteoclasts.
Table 1. Breast cancer-secreted factors that induce differentiated osteoclasts indirectly or directly. Factors may act on osteoblasts to indirectly induce osteoclast differentiation or directly on osteoclasts.
FactorFull NameTarget CellReference
5HTSerotoninOB[69]
ADAMTS1A disintegrin and metalloproteinase with Thrombospondin motifsOB[70]
AREGAmphiregulinOB[70]
CCL2/CCN2Chemokine (C–C motif) ligand 2stromal[71]
CCN3Cysteine-rich protein 61, connective tissue growth factor and nephroblastoma overexpressedOB[72]
CTGFConnective tissue growth factor–[73]
DKK-1Dickkopf-1–[74]
M-CSFMacrophage-colony stimulating factorOC[75]
GM-CSFGranulocyte macrophage-colony stimulating factorOC[76]
HB-EGFHeparin-binding epidermal growth factorOB[70]
IGF-1Insulin-like growth factor–[77]
IL-6Interleukin-6OB, OC[57]
IL-8Interleukin-8OB, OC[58,78]
IL-11Interleukin-11OB, OC[79]
Jagged-1Jagged-1OB, OC[80]
MMP-1Matrix metalloproteinase-1OC[70,81]
MMP-9Matrix metalloproteinase-9–[82]
OSMOncostatin-MOC[83]
–Oxygen-derived free radicalOC[84]
PDGFPlatelet-derived growth factor –[85]
PRDX4Peroxiredoxin-4OC[86]
PTHrPParathyroid hormone-related protein–[55]
RANKLReceptor activator of nuclear factor-κB ligandOC[62,63]
Sema4DSemaforin-4DOB[87]
SHHSonic hedgehogOB, OC[88,89]
TGF-αTransforming growth factor-αOB[70]
TGF-βTransforming growth factor-β–[90]
VCAM1Vascular cell adhesion molecule-1OC[91]
VEGFVascular endothelial growth factorOC[64]
OB, osteoblasts; OC, osteoclasts.
Table
Table 2. PRL-regulated factors in the mammary gland, known to have a role in the bone.
Table 2. PRL-regulated factors in the mammary gland, known to have a role in the bone.
FactorFull Name
PTHrPParathyroid hormone-related protein
VEGFVascular endothelial growth factor
M-CSFMacrophage colony stimulating factor
RANKLreceptor activator of nuclear factor-κB

Share and Cite

MDPI and ACS Style

Shemanko, C.S.; Cong, Y.; Forsyth, A. What Is Breast in the Bone? Int. J. Mol. Sci. 2016, 17, 1764. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101764

AMA Style

Shemanko CS, Cong Y, Forsyth A. What Is Breast in the Bone? International Journal of Molecular Sciences. 2016; 17(10):1764. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101764

Chicago/Turabian Style

Shemanko, Carrie S., Yingying Cong, and Amanda Forsyth. 2016. "What Is Breast in the Bone?" International Journal of Molecular Sciences 17, no. 10: 1764. https://0-doi-org.brum.beds.ac.uk/10.3390/ijms17101764

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop