Hormonal modulation of ESR1 mutant metastasis

Abstract

Estrogen receptor alpha gene ( ESR1 ) mutations occur frequently in ER-positive metastatic breast cancer (MBC), and confer clinical resistance to aromatase inhibitors (AIs). Expression of the ESR1 Y537S mutation induced an epithelial-mesenchymal transition (EMT) with cells exhibiting enhanced migration and invasion potential in vitro . When small subpopulations of Y537S ESR1 mutant cells were injected along with WT parental cells, tumor growth was enhanced with mutant cells becoming the predominant population in distant metastases. Y537S mutant primary xenograft tumors were resistant to the antiestrogen tamoxifen (Tam) as well as to estrogen withdrawal. Y537S ESR1 mutant primary tumors metastasized efficiently in the absence of estrogen; however, Tam treatment significantly inhibited metastasis to distant sites. We identified a 9 gene expression signature which predicted clinical outcomes of ER-positive breast cancer patients, as well as breast cancer metastasis to the lung. Androgen receptor (AR) protein levels were increased in mutant models, and the AR agonist dihydrotestosterone (DHT) significantly inhibited estrogen-regulated gene expression, EMT, and distant metastasis in vivo, suggesting that AR may play a role in distant metastatic progression of ESR1 mutant tumors.

HotspotESR1Mutations Are Multimodal and Contextual Modulators of Breast Cancer Metastasis

“…Together, these results show that hotspot ESR1 mutations confer increased cell-cell attachment under static and fluidic conditions, and that the effect size is dependent upon mutation type and genetic backgrounds. These findings are at odds with increased EMT features (18), and indeed the majority of ESR1 mutant models and tumors did not show increased EMT signature or increased expression of EMT marker genes (Supplementary Fig. S6A-S6D).…”

“…These mechanisms warrant future investigation. In addition, several recent studies uncovered the promising role of androgen receptor (AR) in ESR1 mutant tumors and cell models (18,65), and additional studies are warranted to study de novo interplay between FOXA1, AR and mutant ER.…”

“…Indeed, recent in vivo studies showed that mutant ER can promote metastasis (14,15), and in vitro studies showed a gain of cell motility (15,16) and growth in 3D culture (17). Although epithelial-mesenchymal transition (EMT) has been described as one potential explanation for the Y537S mutant (18), overall mechanisms remain largely unclear. In order to identify personalized therapeutic vulnerabilities in patients harboring ESR1 hotspot mutations, there is an urgent need to decipher the mechanistic underpinnings and precise roles of mutant ER in the metastatic progression using comprehensive approaches and model systems.…”

Estrogen receptor-α signaling in post-natal mammary development and breast cancers

“…Moreover, these mutations not only confer constitutive, hormone-independent activity of ERα but also lead to change in transcriptional responses that mediate cancer progression and confer anti-estrogen resistance by altering the conformation of the ligand-binding domain of ERα, which leads to a stabilized agonist state and an altered antagonist state [268,269]. Expression of the ESR1Y537S mutation also induced an epithelial-mesenchymal transition (EMT) in cells and exhibited enhanced migration [270]. Other mutations, such as K303R, E380Q, S463P, V534E, Y535S, L536R were also found with different frequencies [271][272][273][274][275].…”

Cluster analyses of the TCGA and a TMA dataset using the coexpression of HSP27 and CRYAB improves alignment with clinical-pathological parameters of breast cancer and suggests different epichaperome influences for each sHSP

“…HSP27 binds to both the ER (Chen et al 2004) and human epidermal growth factor receptor 2 (HER2; (Kang et al 2008)) to stabilize them. Estrogen receptor (ER) status is used in classifying breast cancer (Heng et al 2017;Søkilde et al 2019) as well as for prognosis and treatment eg (Gu et al 2020;López-Sánchez et al 2020;Reis-Filho and Pusztai 2011). The availability of the National Cancer Institute Cancer Genome Atlas has facilitated these investigations (Chierici et al 2020;Kan et al 2018;Li et al 2020) and has been used to assess the contribution of individual chaperones on the basis of their normalized expression levels and then identify potential gene networks important in breast cancer (Buttacavoli et al 2021;Klimczak et al 2019;Zoppino et al 2018).…”