CD151-Integrin-Ron Complexes Control Macrophage-Mediated Breast Cancer Malignancy

The goal of this proposal is to understand how the multi-component membrane protein complexes, consisting of CD151, laminin-binding (LB) integrins (á3â1, á6â1, á6â4), and Ron receptor tyrosine kinase, i.e., CD151/L/R complexes, promote the recruitment and activities of pro-tumor M2 phenotype macrophages in human breast cancer. While CD151, LB integrins and Ron have been shown to drive breast cancer progression and metastasis, the underlying mechanisms remain largely undefined. Available observations suggest that the tumor-promoting function of CD151/L/R complexes is related to a special subset of macrophages, known as M2 or M2-like macrophages. Such group of macrophages are highly anti-inflammatory and have been strongly implicated in promoting tumor invasive capabilities and remodeling their microenvironment. Thus, we hypothesize that the CD151/L/R complexes enhance breast cancer malignancy by promoting the pro-metastatic activity of M2 macrophages. To test this hypothesis, we will 1) Evaluate the correlation between infiltrating M2 macrophages and CD151/L/R complexes in breast tumor specimens with respect to tumor grade and subtype as well as patient survival; 2) Assess whether the CD151/L/R complexes play a role in tumor-mediated induction of an anti-inflammatory M2 macrophage phenotype by taking an in vitro co-culture approach with macrophages and mammary tumor cells varying in invasiveness and metastatic capabilities. We expect that the results from our proposed studies will establish strong clinical and biological links between CD151/L/R complexes and the pro-tumor activity of M2 macrophages. Such findings will provide novel insight into the complex cellular network in breast tumors and offer new therapeutic options for treating advanced-stage breast cancer.