Targeting progesterone metabolism in breast cancer with l-proline derived new 14-azasteroids

Breast Cancer cell proliferation is promoted by a variety of mitogenic signals. Classically estrogen is considered as most predominant mitogenic signal in hormone-dependent breast Cancer and progesterone is primarily considered to have protective effect. However, it is suggested that some progesterone metabolite may promote breast Cancer and progesterone metabolites like 5α-pregnane and 4-pregnene could serve as regulators of estrogen-responsiveness of breast Cancer cells. Here, we estimated the potential of alternate targeting of breast Cancer via progesterone signalling. l-Proline derived novel 14-azasteroid compounds were screened against MCF-7 and MDA-MB-231 cell lines using MTT assay. In silico studies, cell cycle, Annexin-V-FITC/PI, JC-1 mitochondrial assay, ROS analysis were performed to analyse the impact of hit compound 3b on breast Cancer cells. Further, we analysed the impact of hit 3b on the progesterone, its metabolites and Enzymes responsible for the conversion of progesterone and its metabolites using ELISA. Data suggests that compound 3b binds and down regulates of 5α-reductase by specifically inhibiting production of progesterone metabolites that are capable of promoting breast Cancer proliferation, epithelial mesenchymal transition and migration. This study establishes the proof of concept and generation of new leads for additional targeting of breast Cancer.

5α-Reductase; Azasteroids; Breast cancer; EMT; Progesterone metabolism.