Blockade of TGF-β inhibits mammary tumor cell viability, migration, and metastases

Abstract

TGF-s are potent inhibitors of epithelial cell proliferation.However, in established carcinomas, autocrine/paracrine TGF- interactions can enhance tumor cell viability and progression.Thus, we studied the effect of a soluble Fc:TGF- type II receptor fusion protein (Fc:TRII) on transgenic and transplantable models of breast cancer metastases.Systemic administration of Fc:TRII did not alter primary mammary tumor latency in MMTV-Polyomavirus middle T antigen transgenic mice.However, Fc:TRII increased apoptosis in primary tumors, while reducing tumor cell motility, intravasation, and lung metastases.These effects correlated with inhibition of Akt activity and FKHRL1 phosphorylation.Fc:TRII also inhibited metastases from transplanted 4T1 and EMT-6 mammary tumors in syngeneic BALB/c mice.Tumor microvessel density in a mouse dorsal skin window chamber was unaffected by Fc:TRII.Therefore, blockade of TGF- signaling may reduce tumor cell viability and migratory potential and represents a testable therapeutic approach against metastatic carcinomas.