Tumor-Derived CCL5 and Breast Cancer Metastasis

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DESCRIPTION (provided by applicant): Metastatic disease in patients with breast cancer is the most common cause of death. For this reason understanding the mechanisms that contribute to metastasis is critical if new therapies are to be developed to stop the metastatic process and the death that ensues. The goal of this project is to determine whether a chemokine that is often produced by freshly isolated breast cancer specimens contributes to metastasis. The chemokine is Regulated Upon Activation Normal T cell Expressed and Secreted (RANTES, CCL5). Tumor-derived CCL5 has been associated with progression in patients with breast cancer and immune suppression in mice. This project will determine whether tumor-derived CCL5 contributes to breast cancer metastasis. For this purpose two murine mammary carcinomas will be used. 4T1 constitutively produces CCL5 and spontaneously metastasizes to the brain, liver and lungs in mice bearing subcutaneously growing tumors. To determine whether tumor-derived CCL5 contributes to the metastatic potential of 4T1 we will use RNA interference to down-regulate CCL5 and the metastatic capability of CCL5+ and CCL5- 4T1 will be determined. In addition to the studies with 4T1 we will use the 168 murine mammary carcinoma which exhibits low metastatic activity and does not produce CCL5. 168 will be transfected with the CCL5 transgene and subsequently the metastatic capability of CCL5+ and CCL5- 168 will be determined. If CCL5 contributes to metastasis then inhibition of tumor-derived CCL5 will correlate with decreased brain, liver and lung metastasis, and up-regulation of CCL5 will correlate with enhanced metastasis of the 4T1 and 168 tumors respectively. Finally, we will determine whether CCL5 contributes to the metastatic capability of the tumor cells by modulating the immune response by delivering the CCL5 modified tumors to nude mice and Balb/c mice depleted of T cell subsets. Collectively, this project will determine whether CCL5 contributes to breast cancer metastasis and whether modulation of immune function is responsible.