Bringing androgens up a NOTCH in breast cancer

Abstract

While it has been known for decades that androgen hormones influence normal breast development and breast carcinogenesis, the underlying mechanisms have only been recently elucidated. To date, most studies have focused on androgen action in breast cancer cell lines, yet these studies represent artificial systems that often do not faithfully replicate/ recapitulate the cellular, molecular and hormonal environments of breast tumours in vivo. It is critical to have a better understanding of how androgens act in the normal mammary gland as well as in in vivo systems that maintain a relevant tumour microenvironment to gain insights into the role of androgens in the modulation of breast cancer development. This in turn will facilitate application of androgen-modulation therapy in breast cancer. This is particularly relevant as current clinical trials focus on inhibiting androgen action as breast cancer therapy but, depending on the steroid receptor profile of the tumour, certain individuals may be better served by selectively stimulating androgen action. Androgen receptor (AR) protein is primarily expressed by the hormone-sensing compartment of normal breast epithelium, commonly referred to as oestrogen receptor alpha (ERa (ESR1))-positive breast epithelial cells, which also express progesterone receptors (PRs) and prolactin receptors and exert powerful developmental influences on adjacent breast epithelial cells. Recent lineage-tracing studies, particularly those focussed on NOTCH signalling, and genetic analysis of cancer risk in the normal breast highlight how signalling via the hormone-sensing compartment can influence normal breast development and breast cancer susceptibility. This provides an impetus to focus on the relationship between androgens, AR and NOTCH signalling and the crosstalk between ERa and PR signalling in the hormone-sensing component of breast epithelium in order to unravel the mechanisms behind the ability of androgens to modulate breast cancer initiation and growth.

Hormone-Sensing Mammary Epithelial Progenitors: Emerging Identity and Hormonal Regulation

“…In contrast, a similar study in normal human breast tissues by Wang et al (2014) found that >90 % of ERα MECs also expressed AR, as determined by dual immunohistochemistry [86]. The latter finding is consistent with the observation that AR positivity is much higher (20-80 %) than ERα positivity (0-20 %) in normal breast tissues (reviewed in [74,87]). Aside from technical sources of variation, likely reasons for such discrepancy between these studies include the age and reproductive status of women at the time of tissue harvest.…”

Complexities of androgen receptor signalling in breast cancer

“…In primates, AR is expressed in all stages of mammary development except for late pregnancy and lactation and appears to show small, non-significant variation across the menstrual cycle (Cheng et al 2005). Ar knockout transgenic models generally indicate that AR is required for normal mammary gland development (reviewed by Hickey et al (2012), Chang et al (2013) and Tarulli et al (2014)). In the human, AR appears to have a protective role in normal breast at least in part by opposing ERa action (Dimitrakakis et al 2003, Eigeliene et al 2012, Ochnik et al 2014.…”

Effects of Tribulus terrestris saponins on exercise performance in overtraining rats and the underlying mechanisms

“…AR binds to specific DNA sequences called androgen response elements (AREs) within the promoter/enhancer regions and regulate target gene transcription by recruiting coactivators or corepressors. Androgens can cross-talk with multiple signal transduction pathways, including phosphatidylinositol 3-kinase(PI3K)/Akt pathway (Lee et al 2015), Wnt/β-catenin signaling pathway (Song and Gelmann 2005), growth hormone (GH)/Insulin-like growth factor I (IGF-I) axis (Wu et al 2006;Zhu and Kyprianou 2008), and Notch signaling (Dubois et al 2012;Tarulli et al 2014). …”