Progesterone activates GPR126 to promote breast cancer development via the Gi pathway

Abstract

Significance The steroid hormone progesterone is highly involved in different physiological–pathophysiological processes, including bone formation and cancer progression. Understanding the working mechanisms, especially identifying the receptors of progesterone hormones, is of great value. In the present study, we identified GPR126 as a membrane receptor for both progesterone and 17-hydroxyprogesterone and triggered its downstream G protein signaling. We further characterized the residues of GPR126 that interact with these two ligands and found that progesterone promoted the progression of a triple-negative breast cancer model through GPR126-dependent Gi-SRC signaling. Therefore, developing antagonists targeting GPR126-Gi may provide an alternative therapeutic option for patients with triple-negative breast cancer.

Association of serum reproductive hormones changes after neoadjuvant chemotherapy with hormone receptors expression alterations and survival outcomes in breast cancer

“…Progesterone also works in hormone receptor-negative breast malignancies. A recent study reported that progesterone accelerated cell growth in vitro and tumorigenesis in vivo in a triple-negative model (41), which supported our view.…”

Phosphatidylserine exposure modulates adhesion GPCR BAI1 (ADGRB1) signaling activity

“…AGPCR signaling is controlled by dynamic changes in the association between the receptors’ NTF and CTF regions, with mechanical forces on the NTF changing the position of the stalk region (also known as the “tethered agonist” or “stachel”) to modulate receptor signaling activity ( 2 , 3 , 4 ). Some AGPCRs are also activated by small-molecule ligands such as steroids ( 58 , 59 ) or bioactive lipids ( 60 ), leading to the emerging view in the field that AGPCRs serve as massive signaling platforms that are crucial for the integration of adhesive, mechanosensory, and chemical stimuli ( 3 ).…”

High Levels of Progesterone Receptor B in MCF-7 Cells Enable Radical Anti-Tumoral and Anti-Estrogenic Effect of Progestin

“…This suggests that progestin-activated PR has dual properties on tumor development, depending on the context. Although progesterone is generally not believed to be carcinogenic in the breast [ 12 , 13 ], it was recently reported to activate GPR126 specifically to promote cell growth through the inhibitory G protein pathway [ 14 ]. Knowledge of the molecular determinant(s) for the pro- or anti-tumoral activity of PR will help the identification of biomarkers that predict the anti-tumoral response to progestin.…”