Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers

Ponnusamy, Suriyan; Asemota, Sarah; Schwartzberg, Lee S.; Guestini, Fouzia; McNamara, Keely May; Pierobon, Mariaelena; Font-Tello, Alba; Qiu, Xintao; Xie, Yingtian; Rao, Prakash K.; Thiyagarajan, Thirumagal; Grimes, Brandy; Johnson, Daniel L.; Fleming, Martin D.; Pritchard, F E; Berry, Michael; Oswaks, Roy; Fine, Richard E.; Brown, Myles; Sasano, Hironobu; Petricoin, Emanuel F.; Long, Henry W.; Narayanan, Ramesh

doi:10.1016/j.isci.2019.10.038

Cited by 29 publications

(33 citation statements)

References 83 publications

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“…The increased combinatorial efficacy of Riluzole and Fulvestrant we observe across diverse cell line models of ER+ breast cancer in vitro is recapitulated in vivo , using primary tumor explant cultures (PDEs) and (to a lesser extent) the ILC-derived HCI-013EI PDX. In the PDX experiment, tumor volume after ~4 weeks of treatment was not significantly different in combination-vs. Fulvestrant-tumors, which we attribute to the good responsiveness of this PDX to Fulvestrant demonstrated in this experiment and by others [45,46]. It should be noted, however, that these published studies report Fulvestrant responsiveness of HCI-013, and not specifically HCI-013EI.…”

Section: Discussionsupporting

confidence: 73%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

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BackgroundResistance to endocrine therapy in estrogen receptor-positive (ER+) breast cancer remains a significant clinical problem. Riluzole is FDA-approved for the treatment of amyotrophic lateral sclerosis. A benzothiazole-based glutamate release inhibitor with several context-dependent mechanism(s) of action, Riluzole has shown anti-tumor activity in multiple malignancies, including melanoma, glioblastoma, and breast cancer. In several (but not all) of these studies, Riluzole-mediated growth inhibition is attributed to increased expression of metabotropic glutamate receptors (mGluRs, GRMs). We recently reported that acquisition of Tamoxifen resistance in a cellular model of invasive lobular breast cancer is accompanied by the upregulation of GRM mRNA expression and growth inhibition by Riluzole.MethodsIn the current study, we tested the ability of Riluzole to reduce cell growth, alone and in combination with endocrine therapy, in a diverse set of ER+ invasive ductal and lobular breast cancer-derived cell lines, primary breast tumor explant cultures, and the estrogen-independent, ESR1-mutated invasive lobular breast cancer patient-derived xenograft model HCI-013EI.ResultsSingle-agent Riluzole suppressed the growth of ER+ invasive ductal and lobular breast cancer cell lines in vitro, inducing a histologic subtype-associated cell cycle arrest (G0-G1 for ductal, G2-M for lobular). In an invasive lobular, endocrine resistant model, Riluzole induced apoptosis and reduced phosphorylation of multiple pro-survival signaling molecules, including Akt/mTOR, CREB, and Src/Fak family kinases. Riluzole in combination with either Fulvestrant or 4-hydroxytamoxifen additively or synergistically suppressed ER+ breast cancer cell growth in vitro. The combination of Riluzole plus Fulvestrant significantly reduced proliferation in primary breast tumor explant cultures, and inhibited HCI-013EI xenograft growth in vivo significantly earlier than Fulvestrant alone.ConclusionsThese findings suggest Riluzole combined with endocrine therapy may offer therapeutic benefit in diverse ER+ breast cancers, including lobular breast cancer.

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Section: Discussionsupporting

confidence: 73%

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Stires

Olukoya

et al. 2020

Preprint

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“…Furthermore, FOXA1 aids in ESR1-mediated recruitment of GRs to estrogen receptor binding regions (Karmakar et al, 2013). Interestingly, AR agonist treatment in breast cancer models reprograms binding of both FOXA1 and ESR (Ponnusamy et al, 2019) suggesting some degree of antagonistic function between the androgen and estrogen receptors. If this is true for asDMPs in sheep, these sites may well represent a conduit through which castrates take on physiologically feminised traits, including delayed aging.…”

Section: Discussionmentioning

confidence: 99%

Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

Sugrue

Narayan

et al. 2020

Preprint

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SUMMARYIn mammals, females generally live longer than males. Nevertheless, the mechanisms underpinning sex-dependent longevity are currently unclear. Epigenetic clocks are powerful biological biomarkers capable of precisely estimating chronological age using only DNA methylation data. These clocks have been used to identify novel factors influencing the aging rate, but few studies have examined the performance of epigenetic clocks in divergent mammalian species. In this study, we developed the first epigenetic clock for domesticated sheep (Ovis aries), and using 185 CpG sites can predict chronological age with a median absolute error of 5.1 months from ear punch and blood samples. We have discovered that castrated male sheep have a decelerated aging rate compared to intact males, mediated at least in part by the removal of androgens. Furthermore, we identified several androgen-sensitive CpG dinucleotides that become progressively hypomethylated with age in intact males, but remain stable in castrated males and females. Many of these androgen sensitive demethylating sites are regulatory in nature and located in genes with known androgen-dependent regulation, such as MKLN1, LMO4 and FN1. Comparable sex-specific methylation differences in MKLN1 also exist in mouse muscle (p=0.003) but not blood, indicating that androgen dependent demethylation exists in multiple mammalian groups, in a tissue-specific manner. In characterising these sites, we identify biologically plausible mechanisms explaining how androgens drive male-accelerated aging.

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“…We further evaluated SAR439859 antitumor activity in HCI013, a patient-derived xenograft (PDX) model that harbors the Y537S ESR1 mutation. The original tumor was obtained from a patient with ERa þ metastatic breast cancer who relapsed on several lines of hormonal therapy, including tamoxifen (37,50,51). Mouse models bearing the HCI013 PDX and treated orally with SAR439859 (2.5-25 mg/kg twice daily) had a dose-dependent inhibition of tumor growth.…”

Section: Downloaded Frommentioning

confidence: 99%

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models

Shomali

Cheng

Sun

et al. 2021

Molecular Cancer Therapeutics

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Primary treatment for estrogen receptor-positive (ER+) breast cancer is endocrine therapy. However, substantial evidence indicates a continued role for ER signaling in tumor progression. Selective estrogen receptor degraders (SERD), such as fulvestrant, induce effective ER signaling inhibition, although clinical studies with fulvestrant report insufficient blockade of ER signaling, possibly due to suboptimal pharmaceutical properties. Furthermore, activating mutations in the ER have emerged as a resistance mechanism to current endocrine therapies. New oral SERDs with improved drug properties are under clinical investigation, but the biological profile that could translate to improved therapeutic benefit remains unclear. Here, we describe the discovery of SAR439859, a novel, orally bioavailable SERD with potent antagonist and degradation activities against both wild-type and mutant Y537S ER. Driven by its fluoropropyl pyrrolidinyl side chain, SAR439859 has demonstrated broader and superior ER antagonist and degrader activities across a large panel of ER+ cells, compared with other SERDs characterized by a cinnamic acid side chain, including improved inhibition of ER signaling and tumor cell growth. Similarly, in vivo treatment with SAR439859 demonstrated significant tumor regression in ER+ breast cancer models, including MCF7-ESR1 wild-type and mutant-Y537S mouse tumors, and HCI013, a patient-derived tamoxifen-resistant xenograft tumor. These findings indicate that SAR439859 may provide therapeutic benefit to patients with ER+ breast cancer, including those who have resistance to endocrine therapy with both wild-type and mutant ER.

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Androgen Receptor Is a Non-canonical Inhibitor of Wild-Type and Mutant Estrogen Receptors in Hormone Receptor-Positive Breast Cancers

Cited by 29 publications

References 83 publications

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Riluzole suppresses growth and enhances response to endocrine therapy in ER+ breast cancer

Castration delays epigenetic aging and feminises DNA methylation at androgen-regulated loci

SAR439859, a Novel Selective Estrogen Receptor Degrader (SERD), Demonstrates Effective and Broad Antitumor Activity in Wild-Type and Mutant ER-Positive Breast Cancer Models

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