The molecular actions of medroxyprogesterone acetate on androgen receptor signalling and the promotion of breast cancer.

The Women’s Health Initiative (WHI) clinical trial was the first randomised, double blind, placebo-controlled disease prevention trial to demonstrate epidemiological evidence of a casual link between the use of combined hormone replacement therapy (cHRT) comprising conjugated equine estrogens (CEE) and the synthetic progestin medroxyprogesterone acetate (MPA) and increased breast cancer risk in post-menopausal women. Since the first WHI report in 2002, other observational studies have demonstrated that it is the addition of the synthetic progestin in the cHRT that is associated with an increase in breast cancer risk. The focus of this thesis was to investigate the following hypothesis formulated in the Dame Roma Mitchell Cancer Research Laboratory, which proposed that MPA possesses antagonistic actions on androgen receptor (AR)-signalling and thereby can disrupt the protective effect of androgens in the breast, thus leading to an increased risk of breast cancer. Androgens have been associated with a growth restrictive role in breast tissue in both humans and animals and are now emerging as key hormonal pathways involved in the pathogenesis of breast cancer. The objectives of this thesis were firstly to determine the relationship between the use of cHRT containing MPA and breast cancer incidence in Australian women, and secondly to perform biological studies to investigate the effect of AR-action in breast epithelial cells. Initial findings described in this thesis led to the identification of a positive association between the use of cHRT preparations containing MPA and breast cancer incidence in Australian women. Subsequent biological based studies were undertaken with non-malignant breast tissues samples from pre- and post- menopausal women in an ex vivo breast explant tissue culture experimental model and the oestrogen receptor (ER), progesterone receptor (PR) and AR positive ZR-75-1 breast cancer cell line to investigate the actions of MPA on AR-signalling and cancer-related intracellular signalling pathways. Collectively these studies demonstrated that the actions of MPA can impede the anti-proliferative actions of DHT in both human postmenopausal non-malignant and malignant breast epithelial cells via AR-mediated actions. Furthermore, the combined actions of DHT and MPA were also shown to de-regulate cancer-related intracellular pathways compared to individual hormone treatments. The findings described in this thesis provide novel results indicating that MPA may promote the development of breast cancer in post-menopausal women taking cHRT via AR-mediated actions and that use of this form of hormone therapy remains a major public health concern.

Author dc:creator

• Ochnik, Aleksandra Monica

Advisors dc:contributor.advisor

• Tilley, Wayne Desmond
• Hickey, Theresa Elizabeth

• synthetic progestin; medroxyprogesterone acetate; hormone replacement therapy; breast cancer

Handle dc:identifier.uri

http://hdl.handle.net/2440/83570

OAI identifier oai:identifier

oai:digital.library.adelaide.edu.au:2440/83570