No abstract

Controlled studies and most observational studies published over the last 5 years suggest that the addition of synthetic progestins to estrogen in hormone replacement therapy (HRT), particularly in continuous-combined regimen, increases the breast cancer (BC) risk compared to estrogen alone. By contrast, a recent study suggests that the addition of natural progesterone in cyclic regimens does not affect BC risk. This finding is consistent with in vivo data suggesting that progesterone does not have a detrimental effect on breast tissue. The increased BC risk found with the addition of synthetic progestins to estrogen could be due to the regimen and/or the kind of progestin used. Continuous-combined regimen inhibits the sloughing of mammary epithelium that occurs after progesterone withdrawal in a cyclic regimen. More importantly, the progestins used (medroxyprogesterone acetate and 19-Nortestosterone-derivatives) are endowed with some non-progesterone-like effects, which can potentiate the proliferative action of estrogens. Particularly relevant seem to be the metabolic and hepatocellular effects (decreased insulin sensitivity, increased levels and activity of insulin-like growth factor-I, and decreased levels of SHBG), which contrast the opposite effects induced by oral estrogen.

No abstract

Metformin is a commonly prescribed type II diabetes medication that exhibits promising anticancer effects. Recently, these effects were found to be associated, at least in part, with a modulation of microRNA expression. However, the mechanisms by which single modulated microRNAs mediate the anticancer effects of metformin are not entirely clear and knowledge of such a process could be vital to maximize the potential therapeutic benefits of this safe and well-tolerated therapy. Our analysis here revealed that the expression of miR-21-5p was downregulated in multiple breast cancer cell lines treated with pharmacologically relevant doses of metformin. Interestingly, the inhibition of miR-21-5p following metformin treatment was also observed in mouse breast cancer xenografts and in sera from 96 breast cancer patients. This modulation occurred at the levels of both pri-miR-21 and pre-miR-21, suggesting transcriptional modulation. Antagomir-mediated ablation of miR-21-5p phenocopied the effects of metformin on both the clonogenicity and migration of the treated cells, while ectopic expression of miR-21-5p had the opposite effect. Mechanistically, this reduction in miR-21-5p enhanced the expression of critical upstream activators of the AMP-activated protein kinase, calcium-binding protein 39-like and Sestrin-1, leading to AMP-activated protein kinase activation and inhibition of mammalian target of rapamycin signaling. Importantly, these effects of metformin were synergistic with those of everolimus, a clinically relevant mammalian target of rapamycin inhibitor, and were independent of the phosphatase and tensin homolog status. This highlights the potential relevance of metformin in combinatorial settings for the treatment of breast cancer.

No abstract