BZDRs promote breast cancer progression through GABRA3-ECM signaling

Abstract

Abstract BZDRs (benzodiazepines and related Z-drugs), are widely used for clinical treatment of insomnia and anxiety disorders. BZDRs act on GABA type A receptors to inhibit neurotransmitters. Previously, we have demonstrated that clinical use of Diazepam (benzodiazepines) and Zolpidem (Z-drugs) are associated with the risk of breast cancer (BRCA) as the treatment time increased. Here, we further investigated the effects and underlying mechanisms of action of BZDRs, Diazepam and Zolpidem, in breast cancer progression. We showed that these BZDRs significantly stimulated BRCA cell migration and invasion, and that long-term usage of BZDRs increased the mortality rate of BRCA patients (p = 0.034). Retrospective studies on patient samples indicate that among 16 GABA receptors examined, GABRA3 (a pro-tumorigenic player) was significantly upregulated during BRCA advancement. BZDRs stimulated GABRA3, which downregulated anti-tumorigenic ECM (extracellular matrix) molecules (S100B, COL6A6 and VIT) and upregulated pro-tumorigenic FBN3 in BRCA cells. Notably, GABRA3-knockdown dramatically suppressed BRCA cell invasion induced by BZDRs, which seemed to work via manipulation of the ECM molecules. Altogether, our data support GABRA3-associated ECM signaling, through the axes of GABRA3-S100B, GABRA3-COL6A6, GABRA3-VIT and GABRA3-FBN3, which might individually or collaboratively play pivotal roles in exacerbating BZDR-mediated breast cancer progression.