A CAF-Fueled TIMP-1/CD63/ITGB1/STAT3 Feedback Loop Promotes Migration and Growth of Breast Cancer Cells

TIMP-1 is one of the many factors that CAFs have been shown to secret. TIMP-1 can act in a tumor-supportive or tumor-suppressive manner. The purpose of this study was to elucidate the role of CAF-secreted TIMP-1 for the effects of CAFs on breast cancer cell behavior. Breast cancer cells were exposed to conditioned medium collected from TIMP-1-secreting CAFs (CAF-CM), and the specific effects of TIMP-1 on protein expression, migration and growth were examined using TIMP-1-specifc siRNA (siTIMP1), recombinant TIMP-1 protein (rhTIMP-1) and TIMP-1 level-rising phorbol ester. We observed that TIMP-1 increased the expression of its binding partner CD63 and induced STAT3 and ERK1/2 activation by cooperating with CD63 and integrin β1. Since TIMP-1 expression was found to be dependent on STAT3, TIMP-1 activated its own expression, resulting in a TIMP-1/CD63/integrin β1/STAT3 feedback loop. IL-6, a classical STAT3 activator, further fueled this loop. Knock-down of each component of the feedback loop prevented the CAF-induced increase in migratory activity and inhibited cellular growth in adherent cultures in the presence and absence of the anti-estrogen fulvestrant. These data show that TIMP-1/CD63/integrin β1/STAT3 plays a role in the effects of CAFs on breast cancer cell behavior.