Abstract
Constitutively active estrogen receptor-α (ER/ESR1) mutations have been identified in approximately one third of ER+ metastatic breast cancer. Although these mutations are known mediators of endocrine resistance, their potential role in promoting metastatic disease has not yet been mechanistically addressed. In this study, we show the presence of ESR1 mutations exclusively in distant, but not local recurrences. In concordance with transcriptomic profiling of ESR1 mutant tumors, genome-edited Y537S and D538G cell models have a reprogrammed cell adhesive gene network via alterations in desmosome/gap junction genes and the TIMP3/MMP axis, which functionally confers enhanced cell-cell contacts while decreased cell-ECM adhesion. Context-dependent migratory phenotypes revealed co-targeting of Wnt and ER as vulnerability. Mutant ESR1 exhibits non-canonical regulation of several metastatic pathways including secondary transactivation and de novo FOXA1-driven chromatin remodeling. Collectively, our data supports evidence for ESR1 mutation-driven metastases and provides insight for future preclinical therapeutic strategies.
Significance Context and allele-dependent transcriptome and cistrome reprogramming in genome-edited ESR1 mutation cell models elicit diverse metastatic phenotypes, including but not limited to alterations in cell adhesion and migration. The gain-of-function mutations can be pharmacologically targeted, and thus may be key components of novel therapeutic treatment strategies for ER-mutant metastatic breast cancer.
Competing Interest Statement
SO and AVL receive research support from AstraZeneca PLC. AVL is employee and consultant with UPMC Enterprises, and member of the Scientific Advisory Board, Stockholder and receives compensation from Ocean Genomics. Tsinghua University paid the stipend of University of Pittsburgh-affiliated foreign scholar Yang Wu from Tsinghua University. MC serves for Pfizer (research support, honoraria), Lilly (advisor, honoraria); Foundation Medicine (honoraria); Sermonix (advisor), G1Therapeutics (advisor) and CytoDyn (advisor). LG receives travel expenses from Menarini SB. BHP has ownership interest and is a paid member of the scientific advisory board of Loxo Oncology and is a paid consultant for Foundation Medicine, Inc, Jackson Labs, Roche, Eli Lilly, Casdin Capital, Astra Zeneca and H3 Biomedicine, and has research funding from Abbvie, Pfizer and Foundation Medicine, Inc. Under separate licensing agreements between Horizon Discovery, LTD and The Johns Hopkins University, BHP is entitled to a share of royalties received by the University on sales of products. The terms of this arrangement are being managed by The Johns Hopkins University in accordance with its conflict-of-interest policies. CD reports grants from European Commission H2020, grants from German Cancer Aid Translational Oncology, during the conduct of the study; personal fees from Novartis, personal fees from Roche, personal fees from MSD Oncology, personal fees from Daiichi Sankyo, personal fees from AstraZeneca, from Molecular Health, grants from Myriad, personal fees from Merck, other from Sividon diagnostics, outside the submitted work. In addition, CD has a patent VMScope digital pathology software with royalties paid, a patent WO2020109570A1 - cancer immunotherapy pending, and a patent WO2015114146A1 and WO2010076322A1- therapy response issued. PJ reports other support from Myriad Genetics, Inc. which is outside the submitted work.