1R03CA215926-01A1 (R03) ApplID: 9443012 | |||
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Title | CXCR3-B-mediated novel growth-inhibitory signals in breast cancer cells | ||
Institution | BOSTON CHILDREN'S HOSPITAL, BOSTON, MA | ||
Principal Investigator | PAL, SOUMITRO | NCI Program Director | Salnikow |
Cancer Activity | Cancer Cell Biology | Division | DCB |
Funded Amount | $88,500 | Project Dates | 06/05/2018 - 06/30/2020 |
Fiscal Year | 2018 | Project Type | Grant |
Research Topics w/ Percent Relevance | Cancer Types w/ Percent Relevance | ||
Cancer (100.0%) Chemotherapy (50.0%) Metastasis (50.0%) |
Breast (100.0%) | ||
Research Type | |||
Cancer Progression & Metastasis Systemic Therapies - Discovery and Development |
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Abstract | |||
PROJECT SUMMARY: New concepts and new targets are needed to fight the deadly disease of breast cancer. Chemokines and their receptors play key roles in chemotaxis, primarily regulating the migration of leukocytes to the site of inflammation and secondary lymphoid organs. However, recent studies clearly suggest that both chemokines and their receptors are expressed in tumor cells (including breast tumor) and play a critical role in modulating tumor growth and progression. The chemokine receptor CXCR3 can have two splice variants with opposite functions. CXCR3- A promotes cell growth, whereas CXCR3-B mediates growth inhibitory signals. Interestingly, the expression of CXCR3-B is down-regulated in breast cancer cells. We have observed through in vitro studies that the induction of CXCR3-B-mediated signal(s) can promote breast cancer cell death by the modulation of apoptosis and autophagy, and down-regulation of the cytoprotective and anti-oxidant molecule heme oxygenase-1 (HO-1). HO- 1 has also been shown to protect cancer cells through increased angiogenesis and by mediating resistance against chemotherapeutic agents. Interestingly, CXCR3-B can have a potential cross-talk with the breast cancer- promoting chemokine receptor CXCR7, possibly through the interaction of their common ligand CXCL11. The goals of this project are: A) to explore the detailed functional significance of CXCR3-B-mediated growth-inhibitory signal(s) in breast cancer cells, with importance to the redox state, B) to study if CXCR3-B can down-regulate CXCR7-induced growth-promoting effects, and C) to examine if the induction of CXCR3-B can restrict breast cancer growth in vivo in a tumor xenograft model. We hypothesize that the induction of CXCR3-B-mediated signals in breast cancer cells will facilitate tumor cell death in vivo through the modulation of redox state and down-regulation of the cytoprotective molecule HO-1, and also through the inhibition of growth-promoting effects of CXCR7. In our specific aims, we will study: 1) the functional significance of CXCR3-B-mediated signals in regulating breast cancer growth and progression, and if it can restrict growth-promoting effects of CXCR7; and 2) the therapeutic effects of CXCR3-B-mediated signals on HO-1-induced breast tumor growth in vivo. Together, our studies can identify how the induction of CXCR3-B-mediated growth-inhibitory signals (through down- regulation of the anti-apoptotic and pro-angiogenic HO-1, and inhibition of CXCR7) can serve as a novel therapeutic approach to restrict the growth of breast cancer, which is highly angiogenic and difficult to be treated. This study should lead to a paradigm shift to identify if CXCR3-B signals can also promote tumor-killing efficiency of chemotherapeutic agents through altered redox states of the tumor cells." |