Progesterone modulates cell growth via integrin αvβ3-dependent pathway in progesterone receptor-negative MDA-MB-231 cells

Progesterone (P₄) plays a pivotal role in regulating the cancer progression of various types, including breast cancer, primarily through its interaction with the P₄ receptor (PR). In PR-negative breast cancer cells, P₄ appears to function in mediating cancer progression, such as cell growth. However, the mechanisms underlying the roles of P₄ in PR-negative breast cancer cells remain incompletely understood. This study aimed to investigate the effects of P₄ on cell proliferation, gene expression, and signal transduction in PR-negative MDA-MB-231 breast cancer cells. P₄-activated genes, associated with proliferation in breast cancer cells, exhibit a stimulating effect on cell growth in PR-negative MDA-MB-231 cells, while demonstrating an inhibitory impact in PR-positive MCF-7 cells. The use of arginine-glycine-aspartate (RGD) peptide successfully blocked P₄-induced extracellular signal-regulated kinase 1/2 (ERK1/2) activation, aligning with computational models of P₄ binding to integrin αvβ3. Disrupting integrin αvβ3 binding with RGD peptide or anti-integrin αvβ3 antibody altered P₄-induced expression of proliferative genes and modified P₄-induced cell growth in breast cancer cells. In conclusion, integrin αvβ3 appears to mediate P₄-induced ERK1/2 signal pathway to regulate proliferation via alteration of proliferation-related gene expression in PR-negative breast cancer cells.