It is now certain that oncogenic signaling and cytoskeleton function are directly involved in breast cancer progression. Our laboratory has determined that overexpression of CD44 variant (CD44v) isoforms [hyaluronan (HA) receptors] appears to confer the malignant properties of increased growth, migration and invasion on breast epithelial cells. In this continuation research proposal, we plan to test the hypothesis that the interaction between CD44v isoforms (CD44v3, CD44v10 and CD44v6/7) and specific signaling activators [e.g. RhoGEFs/RacGEF (Tiam1) and c-Src kinase] plays an important role in HA-mediated oncogenic signaling such as the RhoA-activated ROK pathway, Tiam1-regulated Rac1-PKNgamma kinase pathway and c-Src-induced cortactin and Gab-1/PI3 kinase-AKT pathways. These activation events induce various tumor cell-specific behaviors (e.g. cellular acidification, ECM degradation, cytoskeleton function, tumor cell growth/survival, migration and invasion) leading to breast cancer progression. To test this hypothesis, we plan to use a variety of biochemical, molecular biological techniques and immunohistochemical staining to elucidate HA-CD44v isoform interaction with the various signaling molecules. We will evaluate the functional ramifications of these interactions with respect to specific downstream effector functions (e.g. NHE1-related acidic pH enzyme activation, ankyrin/cortactin-actin binding and PI3 kinase/AKT-mediated biological activities) required for ECM degradation, cytoskeleton function and metastatic tumor cell properties. In addition, we plan to analyze the co-expression of CD44v isoforms and various signaling molecules (e.g. RhoGEF, Tiam1, ROK, PKNgamma and c-Src) in human breast carcinoma tissues obtained from breast cancer patients using immunocytochemistry. We will also employ novel signaling perturbation strategies to impair HA-CD44v isoform-mediated oncogenic signaling by constructing dominant-negative mutants of certain signaling molecules (e.g. ROK, PKNgamma, c-Src, and cortactin). Finally, we will develop therapeutic antisense and small interference RNAs (siRNAs) specifically targeting CD44 in order to effectively block CD44 expression, inhibit HA-mediated downstream oncogenic signaling events and block breast tumor progression. We believe that the information obtained from this proposal has particularly important clinical utility and could establish CD44v isoforms and associated signaling molecules (e.g. RhoGEF, Tiam1, ROK, PKNgamma and c-Src) as important tumor markers for early detection and evaluation of oncogenic potential, as well as allow the development of new drug targets to inhibit breast tumor metastasis and cancer progression.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
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Tumor Cell Biology Study Section (TCB)
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Ault, Grace S
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Northern California Institute Research & Education
San Francisco
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Bourguignon, Lilly Y W; Earle, Christine; Shiina, Marisa (2017) Activation of Matrix Hyaluronan-Mediated CD44 Signaling, Epigenetic Regulation and Chemoresistance in Head and Neck Cancer Stem Cells. Int J Mol Sci 18:
Bourguignon, Lilly Y W; Wong, Gabriel; Shiina, Marisa (2016) Up-regulation of Histone Methyltransferase, DOT1L, by Matrix Hyaluronan Promotes MicroRNA-10 Expression Leading to Tumor Cell Invasion and Chemoresistance in Cancer Stem Cells from Head and Neck Squamous Cell Carcinoma. J Biol Chem 291:10571-85
Bourguignon, Lilly Y W (2016) Matrix Hyaluronan Promotes Specific MicroRNA Upregulation Leading to Drug Resistance and Tumor Progression. Int J Mol Sci 17:517
Hurst, Robert E; Hauser, Paul J; You, Youngjae et al. (2015) Identification of novel drugs to target dormant micrometastases. BMC Cancer 15:404
Bourguignon, Lilly Y W; Shiina, Marisa; Li, Jian-Jian (2014) Hyaluronan-CD44 interaction promotes oncogenic signaling, microRNA functions, chemoresistance, and radiation resistance in cancer stem cells leading to tumor progression. Adv Cancer Res 123:255-75
Chan, John K; Blansit, Kevin; Kiet, Tuyen et al. (2014) The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer. Gynecol Oncol 132:739-44
Chen, Liqun; Bourguignon, Lilly Y W (2014) Hyaluronan-CD44 interaction promotes c-Jun signaling and miRNA21 expression leading to Bcl-2 expression and chemoresistance in breast cancer cells. Mol Cancer 13:52
Bourguignon, Lilly Y W (2014) Matrix hyaluronan-activated CD44 signaling promotes keratinocyte activities and improves abnormal epidermal functions. Am J Pathol 184:1912-9
Bourguignon, Lilly Y W; Wong, Gabriel; Xia, Weiliang et al. (2013) Selective matrix (hyaluronan) interaction with CD44 and RhoGTPase signaling promotes keratinocyte functions and overcomes age-related epidermal dysfunction. J Dermatol Sci 72:32-44
Bourguignon, L Y W; Earle, C; Wong, G et al. (2012) Stem cell marker (Nanog) and Stat-3 signaling promote MicroRNA-21 expression and chemoresistance in hyaluronan/CD44-activated head and neck squamous cell carcinoma cells. Oncogene 31:149-60

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