Trends in Cancer
Volume 2, Issue 1, January 2016, Pages 35-48
Journal home page for Trends in Cancer

Review
Targeting Androgen/Estrogen Receptors Crosstalk in Cancer

https://doi.org/10.1016/j.trecan.2015.12.001Get rights and content

Trends

ERα has a well-established role in estrogen-dependent breast tumor growth, whereas ERβ significantly attenuates cell proliferation and invasion in many cancer types, including breast and prostate.

Emerging evidence indicates that AR signaling exerts inhibitory effects on the growth of normal mammary epithelial cells and plays a protective role in breast carcinogenesis.

There are different potential mechanisms by which ERβ isoforms can modulate AR activity during carcinogenesis and this may affect treatment efficacy in prostate and breast cancers. Among them, the most important is the competition for DNA binding that may alter the recruitment of transcription coregulators, depending on the cancer stage.

The importance of subtle differences among ERβ isoforms, AR, and associated coregulators in different clinical settings should be further explored to identify patient subgroups with specific expression patterns and define the optimal application of AR-directed treatments.

The actions of estrogens are mediated by estrogen receptors, ERα and ERβ. Recent genomic landscaping of ERα- and ERβ-binding sites has revealed important distinctions regarding their transcriptional activity. ERβ and its isoforms have been correlated with endocrine treatment responsiveness in breast tumors, while post-translational modifications, receptor dimerization patterns, and subcellular localization are increasingly recognized as crucial modulators in prostate carcinogenesis. Androgen receptor (AR) is essential for the development and progression of prostate cancer as well as of certain breast cancer types. The balance between the activity of these two hormone receptors and their molecular interactions in different clinical settings is influenced by several coregulators. This comprises a dynamic regulatory network enhancing or limiting the activity of AR-directed treatments in breast and prostate tumorigenesis. In this review, we discuss the molecular background regarding the therapeutic targeting of androgen/estrogen receptor crosstalk in breast and prostate cancer.

Section snippets

ERβ and AR Communicate in Breast and Prostate Cancers

Owing to the endocrine nature of breast and prostate carcinogenesis, targeting of hormone receptors (HRs) remains a treatment cornerstone. Estrogen (ER; ERα and ERβ) and androgen receptor (AR, see Glossary) are members of the steroid nuclear receptor superfamily [1].

In breast and prostate cancers, activation of ERα and AR, respectively, is responsible for enhanced cell proliferation and cell survival, whereas activated ERβ acts as a tumor suppressor [2]. Hence, androgen deprivation therapy

Breast Cancer

Five molecular breast cancer subtypes were identified by microarray gene expression: luminal A, luminal B, basal-like, ERBB-2-enriched, and claudin-low 12, 13. TNBC is defined by the absence of ER, progesterone receptor (PR), and ERBB-2. Although the majority of TNBCs have been classified as basal-like, these two categories are not considered synonymous [14]. Further analysis of TNBCs led to the identification of six subgroups: basal-like 1 and basal-like 2 (BL1, BL2), mesenchymal (M),

Targeting AR in Prostate Carcinogenesis

AR-targeted therapy has evolved since the discovery of prostate cancer dependence on androgen [64] and luteinizing hormone-releasing hormone (LHRH) agonists [65]. The ‘flare’ of testosterone associated with LHRH agonists subsequently led to the development of LHRH antagonists [66], but a paradigm shift in CRPC treatment was abiraterone acetate, an inhibitor of androgen biosynthesis (Table 1) [3]. Likewise, first-generation antiandrogens are initially effective but eventually develop agonist

Targeting AR in Breast Carcinogenesis

AR is expressed in approximately 80% and 60% of primary and metastatic breast carcinomas, respectively [83] and its expression varies across different subtypes 10, 84. An oncogenic role for AR was first described in molecular apocrine breast cancer, an ERα(–)/AR(+) subtype that has a steroid response signature similar to that of ERα(+) breast tumors [85]. Pharmacological modulation of AR was tested in breast cancer with contradictory results. Testosterone was used in nonselected breast cancer

Novel Technologies for Hormone Receptor-Directed Cancer Therapeutics

Modulation of HR activity is quantitatively analyzed by assaying target gene transcription or downstream cascades with various techniques. However, these parameters are indirect and are the result of HR interaction with several TCRs. To study these interactions, methods such as intermolecular free length, yeast two-hybrid, phage display, and colocalization studies in fluorescence microscopy have been employed. One major drawback of these methods is the restriction to study a single

Concluding Remarks

In cancer development and progression, ERα has a well-established role in promoting estrogen-dependent breast tumor growth, whereas ERβ significantly attenuates cell proliferation and progression in a number of cancer types, including breast and prostate. The identification of ERβ isoforms generated new data regarding the role of this receptor in tumor pathogenesis, evolution, and treatment. There are also various potential mechanisms by which ERβ isoforms can modulate AR activity during

Glossary

Androgen receptor (AR)
a nuclear receptor that is activated upon binding the androgenic hormone (testosterone, dihydrotestosterone) in the cytoplasm and then translocates into the nucleus, stimulating transcription of androgen responsive genes. AR plays a key role in prostate and breast cancer.
Castration-resistant prostate cancer (CRPC)
prostate cancer that has undergone enough molecular changes to become resistant to hormone therapy (androgen ablation); however, AR signaling is maintained in

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