Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness–a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer

Madeira, Marcelo; Mattar, André; Logullo, Ângela Flávia; Soares, Fernando Augusto; Gebrim, Luíz Henrique

doi:10.1186/1471-2407-13-425

Cited by 71 publications

(43 citation statements)

References 55 publications

(81 reference statements)

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“…Several mechanisms such as the coactivator-corepressor ratio and tissue-selective modulation of signaling pathways that have been established as mechanisms for the tissue-selectivity of SERMs are also applicable to the SARMs (50,51). The tissue-selective expression of ER-isoforms, (ER-α and ER-β), that often have distinct responses to ligand and thereby provide tissue-selective modulation of ER function by SERMs is unique to SERMs (52). A variety of other molecular mechanisms likely contribute to the observed tissue-selectivity of SARMs.…”

Section: Mechanisms For Sarm Tissue-selectivitymentioning

confidence: 99%

Development of selective androgen receptor modulators (SARMs)

Narayanan

Coss

Dalton

2018

Molecular and Cellular Endocrinology

187

139

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The Androgen Receptor (AR), a member of the steroid hormone receptor family, plays important roles in the physiology and pathology of diverse tissues. AR ligands, which include circulating testosterone and locally synthesized dihydrotestosterone, bind to and activate the AR to elicit their effects. Ubiquitous expression of the AR, metabolism and cross reactivity with other receptors limit broad therapeutic utilization of steroidal androgens. However, the discovery of selective androgen receptor modulators (SARMs) and other tissue-selective nuclear hormone receptor modulators that activate their cognate receptors in a tissue-selective manner provides an opportunity to promote the beneficial effects of androgens and other hormones in target tissues with greatly reduced unwanted side-effects. In the last two decades, significant resources have been dedicated to the discovery and biological characterization of SARMs in an effort to harness the untapped potential of the AR. SARMs have been proposed as treatments of choice for various diseases, including muscle-wasting, breast cancer, and osteoporosis. This review provides insight into the evolution of SARMs from proof-of-concept agents to the cusp of therapeutic use in less than two decades, while covering contemporary views of their mechanisms of action and therapeutic benefits.

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Section: Mechanisms For Sarm Tissue-selectivitymentioning

confidence: 99%

Development of selective androgen receptor modulators (SARMs)

Narayanan

Coss

Dalton

2018

Molecular and Cellular Endocrinology

187

139

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“…The exact role of ER is not clear, however studies have shown that tamoxifen can bind ER and that tamoxifen-bound ER can activate AP1 regulated genes, possibly by altering the balance of associated coactivators and corepressors at the promoter site [135,136]. Indeed, increased ER expression has been reported in tamoxifen resistant breast cancers and data from a recent study suggested that the ratio of ER to ER may be important in predicting response to tamoxifen and anastrozole in the neoadjuvant setting [137,138].…”

Section: Er-independentmentioning

confidence: 99%

Endocrine Resistance in Breast Cancer

Dixon

2014

New Journal of Science

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Around 70% of all breast cancers are estrogen receptor alpha positive and hence their development is highly dependent on estradiol. While the invention of endocrine therapies has revolusioned the treatment of the disease, resistance to therapy eventually occurs in a large number of patients. This paper seeks to illustrate and discuss the complexity and heterogeneity of the mechanisms which underlie resistance and the approaches proposed to combat them. It will also focus on the use and development of methods for predicting which patients are likely to develop resistance.

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“…Loss of ERα and ERβ, and increased ERα to ERβ ratio, as observed in OW and DIO mice, have each been linked with poor breast cancer prognosis in clinical studies (38, 39). Our finding that the ERα to ERβ ratio, a prognostic indicator in breast cancer, can be manipulated by energy balance modulation has not, to our knowledge, been previously reported.…”

Section: Discussionmentioning

confidence: 99%

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice

et al. 2017

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The association between obesity and breast cancer risk and prognosis is well established in ER-positive disease but less clear in HER2-positive disease. Here, we report preclinical evidence suggesting weight maintenance through calorie restriction may limit risk of HER2-positive breast cancer. In female MMTV-HER2/neu transgenic mice, we found that ERα and ERβ expression, mammary tumorigenesis and survival are energy balance-dependent in association with epigenetic reprogramming. Mice were randomized to receive a calorie restriction (CR), overweight (OW)-inducing, or diet-induced obesity (DIO) regimen (n = 27/group). Subsets of mice (n = 4/group/time point) were euthanized after 1, 3 and 5 months to characterize diet-dependent metabolic, transcriptional, and epigenetic perturbations. Remaining mice were followed up to 22 months. Relative to the OW and DIO regimens, CR decreased body weight, adiposity, and serum metabolic hormones as expected, and also elicited an increase in mammary ERα and ERβ expressioñ Increased DNA methylation accompanied this pattern, particularly at CpG dinucleotides located within binding or flanking regions for the transcriptional regulator CCCTC-binding factor (CTCF) of ESR1 and ESR2, consistent with sustained transcriptional activation of ERα and ERβ. Mammary expression of the DNA methylation enzyme DNMT1 was stable in CR mice but increased over time in OW and DIO mice, suggesting CR obviates epigenetic alterations concurrent with chronic excess energy intake. In the survival study, CR elicited a significant suppression in spontaneous mammary tumorigenesis. Overall, our findings suggest a mechanistic rationale to prevent or reverse excess body weight as a strategy to reduce HER2-positive breast cancer risk.

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Estrogen receptor alpha/beta ratio and estrogen receptor beta as predictors of endocrine therapy responsiveness–a randomized neoadjuvant trial comparison between anastrozole and tamoxifen for the treatment of postmenopausal breast cancer

Cited by 71 publications

References 55 publications

Development of selective androgen receptor modulators (SARMs)

Development of selective androgen receptor modulators (SARMs)

Endocrine Resistance in Breast Cancer

Energy Balance Modulation Impacts Epigenetic Reprogramming, ERα and ERβ Expression, and Mammary Tumor Development in MMTV-neu Transgenic Mice

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