Myocardin-related Transcription Factor's Interaction with Serum-response Factor is Critical for Outgrowth Initiation, Progression, and Metastatic Colonization of Breast Cancer Cells

Breast cancer (BC)-related mortality primarily results from metastatic colonization of disseminated cells. Actin polymerization plays an important role in driving post-extravasation metastatic outgrowth of tumor cells. This study examines the role of myocardin-related transcription factor (MRTF)/serum-response (SRF), a transcription system well known for regulation of cytoskeletal genes, in metastatic colonization of BC cells. We demonstrated that co-depletion of MRTF isoforms (MRTF-A and MRTF-B) dramatically impairs single-cell outgrowth ability of BC cells as well as retards growth progression of pre-established BC cell colonies in three-dimensional (3D) cultures. Conversely, overexpression of MRTF-A promotes initiation and progression of tumor-cell outgrowth in vitro primary tumor formation, and metastatic outgrowth of seeded BC cells in vivo and these changes can be dramatically blocked by molecular disruption of MRTF-A's interaction with SRF. Correlated with the outgrowth phenotypes, we further demonstrate MRTF's ability to augment the intrinsic cellular ability to polymerize actin and formation of F-actin-based protrusive structures requiring SRF's interaction. Pharmacological proof-of-concept studies show that small molecules capable of interfering with MRTF/SRF signaling robustly suppresses single-cell outgrowth and progression of pre-established outgrowth of BC cells in vitro as well as experimental metastatic burden of BC cells in vivo. Based on these data, we conclude that MRTF activity potentiates metastatic colonization of BC cells and therefore, targeting MRTF may be a promising strategy to diminish metastatic burden in BC.