Human breast cancer-associated fibroblasts enhance cancer cell proliferation through increased TGF-α cleavage by ADAM17

• ADAM17 was differentially expressed in donor-matched breast tumor and normal breast tissues, and in extracted fibroblasts.
• Fibroblasts extracted from breast tumor secreted higher level of TGF-α than those extracted from matched normal tissue.
• Within the breast tumor microenvironment, ADAM17 mediated TGF-α production in breast stromal fibroblasts.
• ADAM17-cleaved TGF-α promoted breast cancer cell proliferation, instead of migration, via activation of EGFR, Akt and ERK.

We demonstrate here increased expression of ADAM17 protein in cancer-associated fibroblasts (CAFs) extracted from human breast carcinomas compared with donor-matched normal fibroblasts, and TGF-α secretion positively correlates with ADAM17 expression in these cells. In SK-BR-3 cells co-cultured with CAFs, CAF-secreted TGF-α promotes cell proliferation by activation of EGFR, Akt, and ERK, but it does not promote cell migration. Furthermore, anti-TGF-α neutralizing antibodies antagonize the CAF-dependent increase in proliferation and activation of EGFR, Akt and ERK. Thus, pharmacologic inhibition of ADAM17 and TGF-α may have therapeutic potential for the treatment of breast cancer when fibroblast-directed therapy is considered.