UCLA

Stress hormones can promote the spread of breast cancer through the activation of beta-adrenergic signaling. Importantly, prospective clinical trials show that beta-blockers improve prognosis in patients with breast cancer. At the cellular level, our lab recently discovered that beta-adrenergic receptor (βAR) activation regulates mechanical behaviors of highly metastatic triple-negative breast tumor cells in vitro, resulting in decreased deformability, increased invasion, and increased cellular force generation. While beta-adrenergic signaling in fibroblasts has been studied in other tissues, such as cardiac and dermal, less is known about how this signaling impacts mammary fibroblasts. Here we investigate the effects of beta-adrenergic signaling on mammary fibroblasts in the context of cancer. Specifically, I determine the impact of beta-adrenergic signaling on mechanical behaviors of normal mammary fibroblasts as well as cancer-associated fibroblasts (CAFs), which are abundant within the tumor microenvironment (TME) and a major contributor to the mechanical properties of tumors, which can impact treatment efficacy. Our preliminary data in primary human normal mammary fibroblasts show that treatment with βAR agonist isoproterenol increased myosin-light chain 2 (MLC2) phosphorylation, a marker for cellular force generation. We also find that βAR activation increases the expression of extracellular matrix genes, including COL4A2. Additionally, analysis of gene expression data from a prospective clinical trial of breast cancer patients taking the beta-blocker propranolol shows that beta-blockade is associated with regulation of matrisome and cell-matrix interaction genes regulation, including COL4A2, COL6A2, EPCAM, SERPINE, and THBS1. By comparing the effects of βAR activation in normal mammary and breast cancer-associated fibroblasts, will elucidate the fibroblast response to stress signaling in normal and diseased conditions. Findings should provide mechanistic insight into stress hormones' effects on the tumor microenvironment and also guide the development of effective interventions to improve the efficacy of chemotherapy treatments.