transforming-growth-factor-alpha and Triple-Negative-Breast-Neoplasms

MT4-MMP (MMP-17) is a glycosylphosphatidyl inositol-anchored matrix metalloprotease expressed on the surface of cancer cells that promotes tumor growth and metastasis. In this report, we identify MT4-MMP as an important driver of cancer cell proliferation through CDK4 activation and retinoblastoma protein inactivation. We also determine a functional link between MT4-MMP and the growth factor receptor EGFR. Mechanistic experiments revealed direct association of MT4-MMP and its positive effects on EGFR phosphorylation in response to TGFα and EGF in cancer cells. Notably, the effects of MT4-MMP on proliferation and EGFR activation did not rely on metalloprotease activity. Clinically, MT4-MMP and EGFR expressions were correlated in human triple-negative breast cancer specimens. Altogether, our results identify MT4-MMP as a positive modifier of EGFR outside-in signaling that acts to cooperatively drive cancer cell proliferation.

Topics: Animals; Breast Neoplasms; Cell Line, Tumor; Cell Membrane; Cell Proliferation; Chlorocebus aethiops; COS Cells; Cyclin-Dependent Kinase 4; Epidermal Growth Factor; ErbB Receptors; Female; HeLa Cells; Humans; Matrix Metalloproteinases, Membrane-Associated; Mice; Retinoblastoma Protein; Signal Transduction; Transforming Growth Factor alpha; Triple Negative Breast Neoplasms