Breast cancer (BrCa) ranks second in both incidence and cancer deaths for women in the USA. The heterogenous nature of BrCa intensifies its complexity implying that mechanisms change during cancer progression so that certain proteins may step in to support proliferation. Recent advances have revealed significant contributions of chemokines and their receptors in tumor growth, survival after chemotherapy, and organ-specific metastasis. CXCR7 is the latest CXC-chemokine receptor implicated in BrCa growth, although its mechanism of tumor growth enhancement remains unclear. CXCR7 can heterodimerize with CXCR4, bind to SDF-1 (CXCL12), and CXCL11. No direct ligand mediated physiological action has been implicated for CXCR7 in BrCa other than facilitating CXCR4-mediated activity, however, studies in other cancers have implicated CXCR7 in cell proliferation, anti-apoptotic activity and cell-cell adhesion. Our preliminary data shows enhanced but heterogeneous CXCR7 expression in primary breast cancer. More interestingly, CXCR7 is found to colocalize with epidermal growth factor receptor (EGFR), more pronounced in primary breast cancer tissues than normal breast tissue. In vitro experiments demonstrate a link between high CXCR7expression and proliferation in established BrCa cell lines, depletion of which causes cell cycle arrest and reduced activation of MAP kinases, such as ERK1/2. Based on these observations, it is hypothesized that CXCR7 trans-regulates EGFR by physical interaction that leads to enhanced tumor growth and potentially cancer progression. The goal of this project is to understand the mechanism by which CXCR7 modulates tumor cell growth in vitro and in vivo. It is proposed that CXCR7 is an important modulator of cell cycle progression and proliferation of CXCR7 expressing breast cancer cells. CXCR7 may play a critical role in conjunction with EGFR in breast cancer progression. To test these hypotheses, two specific aims are proposed: 1. Demonstrate the biologic consequence of altering the expression of CXCR7 with or without altering its co-receptor CXCR4 in a subset of breast cancer lines. Studies will include verifying that altering CXCR7 expression leads to changes in cell proliferation and other phenotypic changes using RNAi and forced gene expression strategies. 2. Elucidate the mechanism of breast cancer growth by CXCR7- EGFR interaction using both novel and classical techniques. Furthermore, the role of CXCR7 in vivo tumor growth promotion in human breast cancer models will be investigated, using CXCR7 and EGFR inhibitors and/or BrCa cells with stable CXCR7 depletion. This study will provide insight into the unique role of CXCR7 in BrCa and potentially provide a powerful tool for improved strategies to attack cancer. The project will also provide the young investigator thorough research training in breast cancer research and apply the basic mechanistic approach for assessing preclinical efficacy of antitumor therapies.
Despite advancements in surveillance, diagnosis, and treatment, breast cancer causes more than 40,000 deaths annually in the United States. This project breaks new ground in understanding proliferation of breast cancer cells through the molecular mechanism of chemokine receptor (CXCR7) and growth factor receptor (EGFR) interaction. Assessment and disruption of this interaction should provide a novel approach to control breast cancer aggression. The project should help develop novel combination therapy drugs to combat breast cancer.
|Salazar, Nicole; Muñoz, Daniel; Kallifatidis, Georgios et al. (2014) The chemokine receptor CXCR7 interacts with EGFR to promote breast cancer cell proliferation. Mol Cancer 13:198|