Mechanisms of Resistance to Structurally Diverse Antiestrogens Differ under Premenopausal and Postmenopausal Conditions: Evidence from in Vitro Breast Cancer Cell Models

Fan, Ping; Yue, Wei; Wang, Ji Ping; Aiyar, Sarah E.; Li, Yan; Kim, Tae Hyun; Santen, Richard J.

doi:10.1210/en.2008-1195

Cited by 30 publications

(35 citation statements)

References 38 publications

(50 reference statements)

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“…Although BC is a hormone-dependent tumor, the present study found that menopause exhibited no significant effect on endocrine therapy resistance. This conclusion was inconsistent with some previous studies (26). A small sample size, selection criteria and different age-division ranges may also contribute to this conclusion.…”

Section: A B C D Econtrasting

confidence: 90%

Analysis of factors affecting endocrine therapy resistance in breast cancer

Zhang

Chen

2015

Oncology Letters

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Abstract. The present study aimed to identify the factors involved in the resistance to endocrine therapy in breast cancer (BC) patients with a positive estrogen receptor status via the collection of clinical, pathological and immunohistochemical indices. A retrospective survey was performed in patients who experienced the relapse and metastasis of BC between November 2007 and March 2013. A total of 45 patients were enrolled, and the observational duration was 7-84 months. The Kaplan-Meier method was used to create a survival curve, while the log-rank test was used to analyze the survival curve and the Cox regression analysis was used to investigate the associated factors contributing to the resistance to endocrine therapy. Univariate analysis showed that the age of onset, the use of radiotherapy, the endocrine treatment program, and the expression levels of progesterone receptor (PR) and CerbB2 affected the impact of endocrine treatment. The Cox regression analysis indicated that the age of onset, the use of radiotherapy, and the expression levels of PR and CerbB2 affected the disease-free survival time after endocrine therapy. A young age of onset, not receiving radiotherapy, a low expression level of PR and a high expression level of CerbB2 were the risk factors involved in the resistance to endocrine therapy in patients with BC. IntroductionBreast cancer (BC) is a common malignancy that is a serious threat to the health of women. It has been reported that ~1.5 million women are diagnosed with BC annually in the world and that nearly 0.5 million succumb to this disease (1). With accumulating studies on BC, the therapeutic schemes for BC have become much more mature, evolving from the initial local excision to current surgery-based comprehensive treatments, including radiotherapy, chemotherapy, endocrine therapy, biological immune therapy and molecular-targeted therapy.The estrogen receptor (ER) is often found in BC and this cancer is consequently labeled as ER-positive (ERP). Furthermore, as the occurrence and development of BC is so closely associated with the expression of the ER (2), endocrine therapy has been widely used as an effective therapeutic method. In the past few decades, endocrine therapeutic drugs have significantly improved the clinical outcomes of BC patients, as well as their quality of life (3,4). Recently, two multi-center, large-scale, prospective clinical trials further established the positive effect of endocrine therapy in BC treatment (5,6).However, with the extension of endocrine treatment, certain studies found that a few BC patients showed resistance to endocrine therapy. The clinical data indicated that although there were BC-ERP patients who were suitable for endocrine therapy, ~30% of BC-ERP patients exhibited resistance to endocrine drugs in the early stages of treatment (primary resistance), and ~40% BC-ERP of patients showed the effectiveness of endocrine therapy prior to exhibiting gradually reduced sensitivity or resistance with the extension of treatment time (7,8). This E...

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Section: A B C D Econtrasting

confidence: 90%

Analysis of factors affecting endocrine therapy resistance in breast cancer

Zhang

Chen

2015

Oncology Letters

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“…Regardless of the 17b-estradiol (E2) concentration used (10 pmol/L or 1 nmol/L representative of a postmenopausal and premenopausal setting, respectively; ref. 36), elacestrant was able to decrease PGR to a basal level similar to control cells grown in the absence of E2 ( Fig. 1B; Supplementary Fig.…”

Section: T47dsupporting

confidence: 53%

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Bihani

Patel

Arlt

et al. 2017

Clinical Cancer Research

122

105

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Purpose: Estrogen receptor-positive (ER þ ) breast cancers are typically treated with endocrine agents, and dependence on the ER pathway is often retained even after multiple rounds of antiestrogen therapy. Selective estrogen receptor degraders (SERD) are being developed as a strategy to more effectively target ER and exploit ER dependence in these cancers, which includes inhibiting both wild-type and mutant forms of ER. The purpose of this study was to evaluate the efficacy of a novel orally bioavailable SERD, elacestrant (RAD1901), in preclinical models of ER þ breast cancer. Experimental Design: Elacestrant was evaluated as a single agent and in combination with palbociclib or everolimus in multiple ER þ breast cancer models, including several patientderived xenograft models.

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“…It demonstrated that the presence of estrogen is necessary for GPR30 up-regulation/ translocation and might be an important milestone in development of acquired resistance. The importance of estrogen milieu for this process has been very recently confirmed [22]. GPR30 up-regulation can explain the increased sensibility of TAM-R cells to GPR30-specific agonist G1.…”

Section: Discussionmentioning

confidence: 84%

Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells

Ignatov

Roessner

et al. 2009

Breast Cancer Res Treat

141

128

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Tamoxifen is the most frequently used anti-hormonal drug for treatment of women with hormone-dependent breast cancer. The aim of this study is to investigate the mechanism of tamoxifen resistance and the impact of the new estrogen G-protein coupled receptor (GPR30). MCF-7 cells were continuously exposed to tamoxifen for 6 months to induce resistance to the inhibitory effect of tamoxifen. These tamoxifen-resistant cells (TAM-R) exhibited enhanced sensitivity to 17-ss-estradiol and GPR30 agonist, G1, when compared to the parental cells. In TAM-R cells, tamoxifen was able to stimulate the cell growth and MAPK phosphorylation. These effects were abolished by EGFR inhibitor AG1478, GPR30 anti-sense oligonucleotide, and the selective c-Src inhibitor PP2. Only EGFR basal expression was slightly elevated in the TAM-R cells, whereas GPR30 expression and the basal phosphorylation of Akt and MAPK remained unchanged when compared to the parental cells. Interestingly, estrogen treatment significantly increased GPR30 translocation to the cell surface, which was stronger in TAM-R cells. Continuous treatment of MCF-7 cells with GPR30 agonist G1 mimics the long-term treatment with tamoxifen and increases drastically its agonistic activity. This data suggests the important role of GPR30/EGFR receptor signaling in the development of tamoxifen resistance. The inhibition of this pathway is a valid option to improve anti-hormone response in breast cancer.

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Mechanisms of Resistance to Structurally Diverse Antiestrogens Differ under Premenopausal and Postmenopausal Conditions: Evidence from in Vitro Breast Cancer Cell Models

Cited by 30 publications

References 38 publications

Analysis of factors affecting endocrine therapy resistance in breast cancer

Analysis of factors affecting endocrine therapy resistance in breast cancer

Elacestrant (RAD1901), a Selective Estrogen Receptor Degrader (SERD), Has Antitumor Activity in Multiple ER+ Breast Cancer Patient-derived Xenograft Models

Role of GPR30 in the mechanisms of tamoxifen resistance in breast cancer MCF-7 cells

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