Progestogens and Breast Cancer Risk – In Vitro Investigations with Human Benign and Malignant Epithelial Breast Cells

Two recent studies, the Women’s Health Initiative (WHI) and the Million Women Study (MWS), have above all raised concerns over the relationship between progestogens and increased risk of breast cancer in the climacteric and postmenopause (Million Women Study collaborators, 2003; Writing Group, 2002). The Women’s Health Initiative study was terminated early after five years, due to an increased incidence of breast cancer in the group treated with combined estrogen and progestogen therapy (EPT). The MWS concluded that breast cancer risk was increased two-fold in current users of combined HRT compared to a factor of 1.3 for estrogen-only therapy. A crucial role of progestogens in increasing breast cancer risk was supported by the WHI estrogen mono-arm showing no increase but rather a reduction of breast cancer risk, which was significant for patients with more than 80% adherence to study medication (The Women’s Health Initiative Steering Committee, 2004). However, in the French E3N-EPIC trial of over 80 000 postmenopausal women it was reported that hormone therapy containing the progestin medroxyprogesterone acetate or norethisterone was associated with a significant increase in risk of breast cancer, whereas hormone therapy including progesterone and certain other progestins did not induce an increased risk (Fournier et al., 2008). By stimulating the production of survival factors, estradiol (E2) and other steroid hormones may influence cell proliferation. These survival factors include growth factors and cytokines. Epithelial and stromal cell-derived growth factors are understood to be significant in the regulation of breast epithelial cells directly via autocrine, paracrine, juxtacrine or intracrine pathways. Further responses stimulated by growth factors may activate signalling pathways which support the growth of cancer cells (Dickson & Lippman, 1995). Progestogens are conventionally thought to act via the activation of the intracellularlylocated progesterone receptors (PR), PR-A and PR-B. Several in vitro studies indicate that progestogens may exert an antiproliferative effect by activation of these receptors in human breast cancer cells (Cappellatti et al. 1995; Krämer et al., 2006; Schoonen et al., 1995). These data are in contrast to the above mentioned clinical data. Other data suggested a proliferative effect of synthetic progestogens (Catherino et al., 1995; Franke & Vermes, 2003). Thus the mechanisms by which progestogens act on human breast cells remain unclear.