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The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis.

ABSTRACT: BACKGROUND: Estrogens are classified as type I (planar) and type II (angular) based on their structures. In this study we have used triphenylethylenes (TPEs) compounds related to 4OHT to address the hypothesis that the conformation of the liganded estrogen receptor (ER?) may dictate the E2-induced apoptosis of the ER+ breast cancer cells. MATERIALS AND METHODS: ER? positive MCF7:5C cells were used to study the apoptosis induced by E2, 4OHT and TPEs. Growth and apoptosis assay were used to evaluate apoptosis and the ability to reverse the E2-induced apoptosis. ER? protein were measured by western blotting to investigate the destruction of ER? by TPEs in MCF7 cells. ChIP assay were performed to study the in-vivo recruitment of ER? and SRC3 at classical E2-responsive promoter TFF1 (PS2) by TPEs. Molecular modeling was used to predict the binding mode of the TPE to the ER?. RESULTS: TPEs were not only unable to induce efficient apoptosis in MCF7:5C cells but also reversed the E2-induced apoptosis similar to 4OHT. Furthermore, the TPEs and 4OHT did not reduce the ER? protein levels unlike E2. ChIP assay confirmed very weak recruitment of SRC3 despite modest recruitment of ER? in the presence of TPEs. Molecular modeling suggested the TPE would bind in antagonistic mode with the ER?. CONCLUSION: Our results advances the hypothesis that the TPE liganded ER? complex structurally resembles the 4OHT bound ER? and cannot efficiently recruit co-activator SRC3. As a result, the TPE complex cannot induce apoptosis of ER+ breast cancer cells although it may cause growth of the breast cancer cells. The conformation of the estrogen-ER complex differentially controls growth and apoptosis.

SUBMITTER: Maximov P

PROVIDER: S-EPMC3109984 | biostudies-literature | 2011 Mar

REPOSITORIES: biostudies-literature

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The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis.

Maximov Philipp P Sengupta Surojeet S Lewis-Wambi Joan S JS Kim Helen R HR Curpan Ramona F RF Jordan V Craig VC

Hormone molecular biology and clinical investigation 20110301 1

BACKGROUND: Estrogens are classified as type I (planar) and type II (angular) based on their structures. In this study we have used triphenylethylenes (TPEs) compounds related to 4OHT to address the hypothesis that the conformation of the liganded estrogen receptor (ERα) may dictate the E2-induced apoptosis of the ER+ breast cancer cells. MATERIALS AND METHODS: ERα positive MCF7:5C cells were used to study the apoptosis induced by E2, 4OHT and TPEs. Growth and apoptosis assay were used to evalua ...[more]

PMID: 21660224

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Project description:Identification of new molecular targets for the treatment of breast cancer is an important clinical goal, especially for triple-negative breast cancer, which is refractory to existing targeted treatments. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, and thus may be a potential anticancer target. To investigate the AhR as an anticancer target, we conducted a small molecule screen to discover novel AhR ligands with anticancer properties. We identified raloxifene, a selective estrogen receptor (ER) modulator currently used in the clinic for prevention of ER-positive breast cancer and osteoporosis in post-menopausal women, as an AhR activator. Raloxifene directly bound the AhR and induced apoptosis in ER-negative mouse and human hepatoma cells in an AhR-dependent manner, indicating that the AhR is a molecular target of raloxifene and mediates raloxifene-induced apoptosis in the absence of ER. Raloxifene selectively induced apoptosis of triple-negative MDA-MB-231 breast cancer cells compared with non-transformed mammary epithelial cells via the AhR. Combined with recent data showing that raloxifene inhibits triple-negative breast cancer xenografts in vivo (Int J Oncol. 43(3):785-92, 2013), our results support the possibility of repurposing of raloxifene as an AhR-targeted therapeutic for triple-negative breast cancer patients. To this end, we also evaluated the role of AhR expression on survival of patients diagnosed with breast cancer. We found that higher expression of the AhR is significantly associated with increased overall survival and distant metastasis-free survival in both hormone-dependent (ER-positive) and hormone-independent (ER and progesterone receptor (PR)-negative) breast cancers. Together, our data strongly support the possibility of using the AhR as a molecular target for the treatment of hormone-independent breast cancers.

Project description:High-dose synthetic estrogen therapy was the standard treatment of advanced breast cancer for three decades until the discovery of tamoxifen. A range of substituted triphenylethylene synthetic estrogens and diethylstilbestrol were used. It is now known that low doses of estrogens can cause apoptosis in long-term estrogen deprived (LTED) breast cancer cells resistant to antiestrogens. This action of estrogen can explain the reduced breast cancer incidence in postmenopausal women over 60 who are taking conjugated equine estrogens and the beneficial effect of low-dose estrogen treatment of patients with acquired aromatase inhibitor resistance in clinical trials. To decipher the molecular mechanism of estrogens at the estrogen receptor (ER) complex by different types of estrogens-planar [17β-estradiol (E2)] and angular triphenylethylene (TPE) derivatives-we have synthesized a small series of compounds with either no substitutions on the TPE phenyl ring containing the antiestrogenic side chain of endoxifen or a free hydroxyl. In the first week of treatment with E2 the LTED cells undergo apoptosis completely. By contrast, the test TPE derivatives act as antiestrogens with a free para-hydroxyl on the phenyl ring that contains an antiestrogenic side chain in endoxifen. This inhibits early E2-induced apoptosis if a free hydroxyl is present. No substitution at the site occupied by the antiestrogenic side chain of endoxifen results in early apoptosis similar to planar E2 The TPE compounds recruit coregulators to the ER differentially and predictably, leading to delayed apoptosis in these cells. SIGNIFICANCE STATEMENT: In this paper we investigate the role of the structure-function relationship of a panel of synthetic triphenylethylene (TPE) derivatives and a novel mechanism of estrogen-induced cell death in breast cancer, which is now clinically relevant. Our study indicates that these TPE derivatives, depending on the positioning of the hydroxyl groups, induce various conformations of the estrogen receptor's ligand-binding domain, which in turn produces differential recruitment of coregulators and subsequently different apoptotic effects on the antiestrogen-resistant breast cancer cells.

Dataset Information

The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis.

Publications

The Conformation of the Estrogen Receptor Directs Estrogen-Induced Apoptosis in Breast Cancer: A Hypothesis.

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