Postmenopausal breast cancer, androgens, and aromatase inhibitors

Abstract

Recent data can help to better define the long debated relationship between androgens and breast cancer (BC) after menopause. We reviewed the available literature data on: the origin of androgens after menopause, the association between circulating androgens and BC incidence and recurrence, the relationship between circulating and intratumoral hormones, the prognostic significance of the presence of androgen receptors (ARs) in the different BC subtypes, the androgen effect on BC cell lines, and the relationship between androgens and aromatase inhibitors. Epidemiological, clinical, and preclinical data on the role of androgens and of ARs on estrogen receptor (ER)-negative BC are somewhat controversial. However, most preclinical studies suggest that activated ARs, when present, have a proliferative effect, particularly in HER2 expressing cell lines, due to the cross-talk between AR and HER2 pathways. As regards ER-positive BC, epidemiological studies associate androgen levels with increased incidence and risk of recurrences, whilst clinical studies associate the AR positivity with a better prognosis. Preclinical studies suggest that the action of androgens is bidirectional: mainly proliferative, because circulating androgens are the precursors of estrogens, but also anti-proliferative, because AR activation restrains ER activity. The relative increase of androgenic action that follows the blocking of androgen aromatization into estrogens by aromatase inhibitors (AIs), could contribute to their therapeutic efficacy in AR-positive cases. Available data, although defining a complex picture, suggest that circulating androgen levels are clinically relevant, particularly when AIs are used.

Alcohol Consumption and Risk of Breast Cancer by Tumor Receptor Expression

“…AR has important physiological effects in normal breast development, is expressed in >70% of malignant breast tissue [12,13], and has been reported as a favorable prognostic factor for breast cancer survival [14]. Although studies addressing the role of AR in breast cancer etiology are limited, pre-diagnostic circulating levels of androgens are consistently positively associated with breast cancer risk [15–17].…”

A Targetable Androgen Receptor–Positive Breast Cancer Subtype Hidden Among the Triple-Negative Cancers

“…49 Angiogenesis inhibitors are not particularly specific for TNBC, however, and may be associated with variable response with a variety of other carcinomas as well. AR þ , TRIPLE-NEGATIVE BREAST CARCINOMA Along with increasing interest in the discovery of novel therapeutic targets for the highly heterogeneous population of breast cancers, [54][55][56][57] interest in AR as a target is also increasing. Recent and emerging data suggest that AR may play a role in the pathogenesis of breast carcinoma and could be considered a potential target for therapy, particularly in TNBC.…”

“…Frequently coexpressed with ER, PR, and/or HER2, AR is the most commonly expressed (47%-90%) receptor among all types of breast cancer, 13,17,57,58 with a frequency of 10% to 75% among TNBC cases. 59,60 Moinfar et al 61 found AR expression in 90% of grade 1 invasive breast cancers compared with 47% of grade 3 invasive breast carcinomas and concluded that AR is the most frequently expressed marker even among high-grade breast carcinomas.…”

“…Although the reported expression rate for AR has varied widely-probably because of different cutoff points [13][14][15][16][17]59,62 used in various studies-it has been suggested that its expression in TNBC has prognostic value. 57,60,62,63 Using the 1% criterion for ER, PR, and AR positivity, along with a 30% threshold for HER2 immunohistochemical evaluation, a recent study of 325 invasive breast cancers found 21 cases (6.5%) that were only AR positive and 33 that were AR and HER2 positive. 64 Interestingly, even among BRCA1-mutated breast cancers, about 1 in 5 tumors that are ER À and PR À express AR.…”

Comparison patterns of 4 T1 antigens recognized by humoral immune response mediated by IgG and IgM antibodies in female and male mice with breast cancer using 2D-immnunoblots

“…Epidemiological studies have reported that androgens stimulate cell proliferation and promote the development of cancer (Key et al, 2002). Prospective cohort studies also suggest that there the risk of breast cancer is greater with high levels of circulating androgens -directly by increasing cellular growth and proliferation via the androgen receptor or indirectly through their aromatization to estrogens (Campagnoli et al, 2013;Kotsopoulos and Narod, 2012).…”