Progesterone signaling in breast cancer

Progesterone (P4) is important for normal mammary gland development, function and menstrual control. However, P4 and its receptors (PRs) in breast cancer etiology continue to be understudied and its role in breast cancer remains controversial. P4 has historically been associated with classical-signaling through nuclear receptors, however non-classical P4 signaling via membrane receptors have been described only to some extent. Progestogens have the ability to bind to nuclear and membrane receptors and studies have demonstrated that both can promote breast cancer cell proliferation and breast tumor growth. Increased expression of the progesterone receptor membrane component 1 (PGRMC1) is frequently observed in ER+ and triple negative breast cancers (TNBCs). However, its role as a potential oncogene and therapeutic target has not been studied extensively. Using a chemical inhibitor (AG-205) and RNA interference, we studied the downstream signaling mechanisms of PGRMC1 in different breast cancer subtypes. MTS, flowcytometry, qPCR, western blotting, confocal microscopy, immunohistochemistry, phospho-proteome and miRNome analysis as well as in silico analysis of online datasets were performed which demonstrated that, 1) PGRMC1 plays a prominent role in regulating growth of cancer cells by altering the PI3K/AKT/mTOR and EGFR signaling mechanisms in both ER+ and TNBC cells. 2) Human miRNome analysis, identified miRNA target genes to be direct targets of upregulated miRNAs following PGRMC1 impairment in TNBCs. 3) Finally, targeting PR, ER⍺, and PGRMC1 confirmed that a crosstalk between classical and non-classical signaling mechanisms exists in ER+ breast cancer cells that could enhance the growth of ER+/PR+/PGRMC1 overexpressing tumors. In conclusion, the data demonstrates that PGRMC1 is an oncogene and could be a potential therapeutic target for breast cancers.