Browsing by Author "Eksteen, Anishka"
Now showing 1 - 1 of 1
Results Per Page
Sort Options
- ItemInvestigating the role of inflammation, progestins and steroid receptors in breast cancer(Stellenbosch : Stellenbosch University, 2019-04) Eksteen, Anishka; Africander, Donita; Verhoog, Nicolette J. D.; Stellenbosch University. Faculty of Science. Dept. of Biochemistry.ENGLISH ABSTRACT: Progestins are used by women all over the world in menopausal hormone therapy (HT) and contraception. Numerous clinical trials have, however, reported that some progestins are associated with an increased risk for developing breast cancer. Although multiple progestins with different chemical structures and biological activities have been synthesised, not all progestins have been evaluated for increased breast cancer risk. Obesity-related inflammation is also strongly associated with increased breast cancer risk, particularly amongst postmenopausal women. This increased inflammatory state is characterised by enhanced production of pro-inflammatory cytokines, such as interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNFα). Both these inflammatory mediators have been implicated in breast cancer development and progression. However, the exact mechanism whereby inflammation and progestins contribute to breast cancer risk is yet to be established. The aim of this study was thus to investigate the effects of different progestins, in the absence and presence of IL-6 or TNFα, on the proliferation, apoptosis, migration and invasion of breast cancer cells. Given that some progestins can interact with multiple steroid receptors, all of which are known to play important roles in breast cancer biology, the first part of the study investigated effects on steroid receptor expression in the T47D breast cancer cell line. Western blot analysis showed that all the progestins decreased the expression of the estrogen receptor (ER)-subtypes, progesterone receptor (PR)-isoforms and the androgen receptor (AR), while no effects were observed on the expression of the glucocorticoid receptor (GR). This study also showed that IL-6 has no effect on steroid receptor expression levels, while TNFα increased the expression of the GR. Results from this study also show that the selected progestins differentially increased cell survival of T47D and MCF-7 BUS breast cancer cells, while all progestins and both inflammatory mediators increased the migration of T47D breast cancer cells. IL-6 had no effect on cell survival of either cell line, while TNFα decreased the survival of the MCF-7 BUS cells. In addition, the progestins medroxyprogesterone acetate (MPA) and drospirenone (DRSP), as well as IL-6, appeared to increase invasion of the MDA-MB-231 breast cancer cell line. In contrast, TNFα appeared to decrease invasion of the MDA-MB-231 cells. This study is the first to show that none of the progestin-mediated effects on steroid receptor expression, proliferation, apoptosis and migration were modulated by either IL-6 or TNFα. On the other hand, TNFα appeared to decrease the progestin-induced effects on the invasion of the MDA MB-231 breast cancer cell line. Taken together, the results show that even though the progestins and the pro inflammatory cytokines may differentially affect breast cancer growth and survival, all the selected progestins, as well as IL-6 and TNFα, increase migration of T47D breast cancer cells. These results suggest that all these progestins and the inflammatory mediators may possibly increase the risk of developing metastatic breast cancer. Finally, the results obtained in this study indicate that the effects of the progestins on steroid receptor expression and hallmarks of cancer, were not exacerbated by the addition of the inflammatory mediators, suggesting that the combination of inflammation and progestins used in HT does not further increase breast cancer risk.