Evidence of androgen action in endometrial and ovarian cancers

Abstract

Endometrial cancer (EC) and ovarian cancer are common gynaecological malignancies. The impact of androgen action in these cancers is poorly understood; however, there is emerging evidence to suggest that targeting androgen signalling may be of therapeutic benefit. Epidemiological evidence suggests that there is an increased risk of EC associated with exposure to elevated levels of androgens, and genetic variants in genes related to both androgen biosynthesis and action are associated with an increased risk of both EC and ovarian cancer. Androgen receptors (ARs) may be a potential therapeutic target in EC due to reported anti-proliferative activities of androgens. By contrast, androgens may promote growth of some ovarian cancers and anti-androgen therapy has been proposed. Introduction of new therapies targeting ARs expressed in EC or ovarian cancer will require a much greater understanding of the impacts of cell context-specific AR-dependent signalling and how ARs can crosstalk with other steroid receptors during progression of disease. This review considers the evidence that androgens may be important in the aetiology of EC and ovarian cancer with discussion of evidence for androgen action in normal and malignant endometrial and ovarian tissue.

Endogenous androgens and risk of epithelial invasive ovarian cancer by tumor characteristics in the European Prospective Investigation into Cancer and Nutrition

“…testosterone, DHT) may play a role in ovarian carcinogenesis. 31 However, AR expression in serous carcinomas was associated with improved survival in one study (n 5 90). 35 Androgens may have a direct impact on ovarian carcinogenesis, or act via their function as precursors to estrogens.…”

“…Androgen receptors (AR) and estrogen receptors (ER) are expressed throughout the reproductive system including ovaries, the fallopian tubes and endometrium. 31,32 Androstenedione and DHEAS have low binding affinity for AR while testosterone and dihydrotestosterone (DHT) have highest AR affinity and androgenic activity. Prior research suggests EOC tumors express the AR with differences by histological subtype.…”

“…An incidence density sampling protocol was used, such that controls could include subjects who became a case later in time and each control could be sampled more than once. Cases and controls in both study phases were matched on: study recruitment center, age at blood donation (66 months), time of the day of blood collection (61 h), fasting status (<3 h, 3-6 h, >6 h), and menopausal status at blood collection (premenopausal, perimenopausal, postmenopausal), as well as menstrual cycle phase for premenopausal women ("early follicular" (days 0-7 of the cycle), "late follicular" (days 8-11), "peri-ovulatory" (days 12-16), "mid-luteal" (days [20][21][22][23][24], and "other luteal" (days 17-19 or days [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40]. Cases missing data on phase of menstrual cycle were matched to controls with missing information on menstrual cycle phase.…”

Glandular epithelial AR inactivation enhances PTEN deletion-induced uterine pathology

“…As androgens may also have roles in uterine pathology (Gibson et al 2014) and AR is expressed in many uterine cancers notably of epithelial cells (Ito et al 2002), we investigated the role of AR-mediated androgen action confined to uterine glandular epithelium in experimental, PTEN deletion-induced uterine pathology. Our study has demonstrated that glandular epithelial AR inactivation significantly enhanced and accelerated the progression of PTEN deletion-induced uterine pathology.…”

In situ androgen and estrogen biosynthesis in endometrial cancer: focus on androgen actions and intratumoral production

“…In the nonmalignant endometrium, AR was reported to be expressed in the endometrium throughout the menstrual cycle (Mertens et al 2001, Apparao et al 2002, Ito et al 2002, Marshall et al 2011, Gibson et al 2014. The status of AR immunoreactivity in stromal cells is higher than that of epithelial AR throughout the menstrual cycle (Apparao et al 2002).…”