The Divergent Function of Androgen Receptor in Breast Cancer; Analysis of Steroid Mediators and Tumor Intracrinology

Abstract

Androgen receptor (AR) is the most widely expressed steroid receptor protein in normal breast tissue and is detectable in approximately 90% of primary breast cancers and 75% of metastatic lesions. However, the role of AR in breast cancer development and progression is mired in controversy with evidence suggesting it can either inhibit or promote breast tumorigenesis. Studies have shown it to antagonize estrogen receptor alpha (ERα) DNA binding, thereby preventing pro-proliferative gene transcription; whilst others have demonstrated AR to take on the mantle of a pseudo ERα particularly in the setting of triple negative breast cancer. Evidence for a potentiating role of AR in the development of endocrine resistant breast cancer has also been mounting with reports associating high AR expression with poor response to endocrine treatment. The resurgence of interest into the function of AR in breast cancer has resulted in various emergent clinical trials evaluating anti-AR therapy and selective androgen receptor modulators in the treatment of advanced breast cancer. Trials have reported varied response rates dependent upon subtype with overall clinical benefit rates of ~19-29% for anti-androgen monotherapy, suggesting that with enhanced patient stratification AR could prove efficacious as a breast cancer therapy. Androgens and AR have been reported to facilitate tumor stemness in some cancers; a process which may be mediated through genomic or non-genomic actions of the AR, with the latter mechanism being relatively unexplored in breast cancer. Steroidogenic ligands of the AR are produced in females by the gonads and as sex-steroid precursors secreted from the adrenal glands. These androgens provide an abundant reservoir from which all estrogens are subsequently synthesized and their levels are undiminished in the event of standard hormonal therapeutic intervention in breast cancer. Steroid levels are known to be altered by lifestyle factors such as diet and exercise; understanding their potential role in dictating the function of AR in breast cancer development could therefore have wide-ranging effects in prevention and treatment of this disease. This review will outline the endogenous biochemical drivers of both genomic and non-genomic AR activation and how these may be modulated by current hormonal therapies.

Keywords: androgen receptor; breast cancer; intracrinology; non-genomic signaling; steroids.

Figure 1

(A) A core from a breast tumor tissue microarray depicting normal ductal structures within the mammary gland that have been stained immunohistochemically for AR (Novocastra, Leica). (B) A magnified region of normal breast ducts. The outer myoepithelial layer of cells are devoid of AR, in contrast ~30–40% of the inner luminal epithelial cells express high levels of AR protein.

Figure 2

Prohormones are secreted from the adrenal zona reticularis and ovarian theca cells in post-menopausal women. DHEA and 4-dione can be further metabolized intracellularly in peripheral tissues by hydroxysteroid dehydrogenase/isomerases, reductases, and aromatase to generate both androgenic and estrogenic metabolites.

Figure 3

Representative images depicting the range and heterogeneity of AR protein expression within breast tumors. The panel shows ER+ve positive tumors with (A) Low AR expression, (B) Moderate AR expression, (C) Heterogeneous AR expression and (D) High AR expression.

Figure 4

(i) Mechanisms of AR ERα mediated gene transcription in AR+ve ERα +ve breast cancer. Many studies have reported on the dynamic relationship between ER and AR DNA binding and direct interactions in breast cancer. AR and ERα can transcriptionally regulate each other through heterodimerization and binding to the same DNA sequence. AR ER target gene transcription is also influenced by the level of steroid present and overexpression of receptors. (ii) Mechanisms of androgen mediated signaling reported in ERα negative Her2 amplified breast cancer studies. In triple negative breast cancer with Her2 amplification, androgens appear to initiate 2^nd messenger signaling cascades. This often results in a feedback loop and in this way drives tumor progression.

Figure 5

Summary of known diet and lifestyle factors associated with either increased or decreased breast cancer risk. Exercise, is particularly notable, as it is associated with a reduction in the levels of circulating androgens irrespective of weight-loss. Steroid structure Source: https://pubchem.ncbi.nlm.nih.gov/. Description: Data deposited in or computed by PubChem. Visceral adipose image source: Cook A, Cowan C. Adipose. 2009 Mar 31. In: StemBook [Internet]. Cambridge (MA): Harvard Stem Cell Institute; 2008. Figure 1, White adipose distribution in the body. Available from: https://www.ncbi.nlm.nih.gov/books/NBK27053/figure/adipose.F1/ doi: 10.3824/stembook.1.40.1.