Progesterone prevents radiation-induced apoptosis in breast cancer cells

Abstract

Sex steroid hormones play an essential role in the control of homeostasis in the mammary gland. Although the involvement of progesterone in cellular proliferation and differentiation is well established, its exact role in the control of cell death still remains unclear. As dysregulation of the apoptotic process plays an important role in the pathogenesis of breast cancer, we investigated the regulation of apoptosis by progesterone in various breast cancer cell lines. Our results show that progesterone treatment protects against radiation-induced apoptosis. This prevention appears to be mediated by the progesterone receptor and is unrelated to p53 status. There is also no correlation with the intrinsic hormonal effect on cell proliferation, as the presence of cells in a particular phase of the cell cycle. Surprisingly, progesterone partly allows bypassing of the irradiation-induced growth arrest in G 2 /M in PgR þ cells, leading to an increase in cell proliferation after irradiation. One consequence of this effect is a higher rate of chromosome damage in these proliferating progesterone-treated cells compared to what is observed in untreated irradiated cells. We propose that progesterone, by inhibiting apoptosis and promoting the proliferation of cells with DNA damage, potentially facilitates the emergence of genetic mutations that may play a role in malignant transformation.

Generation of Breast Cancer Stem Cells by Steroid Hormones in Irradiated Human Mammary Cell Lines

“…1B, D, F). In accordance with our earlier results [6], progesterone treatment significantly reduced the radiation-induced cell death in T47D cells. Interestingly, a similar protective effect of progesterone was also observed in MCF10A cells.…”

“…T-47D and MCF7 breast cancer cell lines were maintained as previously [6]in Dulbecco’s modified Eagle medium (DMEM) with 4.5 g/L glucose, 0.11 g/L sodium pyruvate, glutamate (GlutaMAX 1t) and pyridoxine, supplemented with 5% fetal calf serum, penicillin and streptomycin. Non-tumorigenic MCF10A breast epithelial cells [22] were maintained in DMEM/F12 supplemented with 5% horse serum, 20 ng/mL epidermal growth factor (EGF), 10 µg/mL insulin, 100 µg/mL hydrocortisone and 10 ng/mL cholera toxin.…”

“…The interplay between steroid hormones and radiation-induced risks has been described. For example, we have shown that progesterone protects cultured mammary cells against radiation-induced apoptosis and increases the number of proliferating cells containing chromosomal damage [6]. However, our knowledge of hormonal action in the irradiated breast is far for complete and new discoveries are challenging some established paradigms.…”

Linking DNA Damage and Hormone Signaling Pathways in Cancer

“…However, steroid hormones have been selectively shown to promote transformation [19, 20], as well as generate complex genomic rearrangements through induction of double-strand breaks (DSBs) that are associated with tumorigenesis [21–24]. Conversely, hormone signaling has also been shown to stabilize DNA [25, 26] and be chemopreventive [27], thus obfuscating the ability to generalize the effects of any one NR on genome stability. Additionally, some NR antagonists (e.g.…”

Role of the progesterone receptor for paclitaxel resistance in primary breast cancer

“…Nevertheless, the antiapoptotic influence of the PR is well documented. For instance, serum depletion-induced apoptosis was inhibited by progesterone treatment (Ory et al, 2001) and also radiation-induced apoptosis could be antagonised via PR (Vares et al, 2004) in breast cancer cell lines.…”