Functions of chemokine and TGF-B signaling in the breast cancer microenvironment

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DESCRIPTION (provided by applicant): Fibroblasts are a major cellular component of the tumor microenvironment and influence cancer cell behavior directly and indirectly through secretion of soluble factors, including growth regulators, angiogenic factors and chemokines. While genetic alterations in breast fibroblasts may exert pro-tumorigenic effects, little is known of the cellular and molecular signals that regulate fibroblast functions in the breast cancer microenvironment. De-regulation of TGF-B signaling significantly contributes to metastatic breast cancer, and may also enhance expression of chemokines in breast fibroblasts, to promote cancer progression. Based on previous studies and preliminary studies, we hypothesize that inflammatory chemokine expression in fibroblasts including CCL2 and CXCL1 mediate epithelial cell and immune cell motility and invasiveness to promote breast cancer progression. The objective of this proposal is determine the functions of chemokines, which are normally suppressed by TGF-B signaling, in fibroblast interactions with tumor cells during breast cancer progression. The following Specific Aims are proposed to address this hypothesis: Specific Aim 1: To determine the mechanisms of CCL2 and CXCL1 inflammatory chemokine expression in mammary fibroblasts as it relates to TGF-B signaling using cell biology, molecular and biochemical approaches. Specific Aim 2: To determine the functional contribution of CCL2 and CXCL1 chemokines expressed by mammary fibroblasts in breast cancer growth, invasion and metastasis, using transplantable and transgenic mouse models of breast cancer, cell biological and biochemical approaches. Specific Aim 3 : To determine the contribution of CCL2 and CXCL1 chemokines expressed by mammary fibroblasts in immune cell trafficking, homing and recruitment in breast cancer progression using transplantable mouse models of cancer, cell biological and biochemical approaches. Specific Aim 1 would be addressed during the mentored phase, while Aims 2 and 3 would be addressed during the mentored and independence phases. This research will address the functions and mechanisms through which inflammatory chemokine expression in fibroblasts contributes to breast cancer. Through these studies, we seek to further understand the functions of stromal cells in the host microenvironment, and how the host microenvironment contributes to tumor progression at the molecular, cellular and in vivo levels. By further understanding the role of the tumor microenvironment in cancer progression, it will be possible to identify new molecular targets for therapy and to develop improved methods for diagnosing and treating metastatic breast cancer.