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Does Heat Shock Protein 27 (Hsp27) Play Any Immunomodulatory Role in Breast Cancer?
A. Background: Improving the therapeutic strategy for management of breast cancer requires a better understanding of the biology of breast cancer cells as well as exploring the mechanisms used by tumor cells to escape immune surveillance. Recently, we have demonstrated that heat shock protein (hsp27) can induce IL-10, an anti-inflammatory cytokine, in human monocytes. IL-10 also inhibits the development of dendritic cells (DC) that are essential for generation of tumor specific cytotoxic T lymphocytes (CTL). More recently, we developed some novel findings that hsp27 can inhibit monocyte to DC differentiation. Moreover, serum levels of hsp27 are suggested as increased in breast cancer patients. In addition, we have preliminary data that some breast cancer cell lines secrete hsp27. B. Objectives/Hypothesis: We hypothesize that in vivo circulatory hsp27 levels are increased during the progression of breast cancer, causing defective DC activity and deficient breast cancer - specific CTL development, thereby establishing an immunological escape mechanism for tumors. C. Specific Aims: I.Determine the correlation between serum hsp27 levels and the progression of the disease and also explore the possible mechanisms for elevated serum hsp27 levels in breast cancer. II. Elucidate the role of hsp27 in modulating immune responses in breast cancer. D. Study Design: Specific Aim I: Levels of CA 15-3 (a long-tested biomarker with fairly reliable sensitivity) and hsp27 will be simultaneously measured in patients’ serum during the course of the disease to test whether hsp27 is a better prognostic marker. Possible sources of increased hsp27 levels will also be evaluated. Specific Aim II.a) Determine whether hsp27 can inhibit breast cancer specific CTL generation. b) Assess patients’ DC and CTL functions and correlate any defect in these parameters to their (exposure to) in vivo serum hsp27 levels. c) Evaluate the possible inhibitory effect of patients’ serum (containing high hsp27?) on monocyte to DC differentiation. E. Potential Outcomes and Benefits of the Research: Our proposal will reveal: 1) the possibility of using serum hsp27 levels as a better prognostic biomarker for breast cancer, which may be helpful in assessing the responses to different therapies, and 2) the understanding of one of the unexplored immune escape mechanisms used by breast cancer cells that may help in designing a better strategy for treatment of breast cancer.
A. Background: Breast cancer is the leading cause of cancer death in women. Despite advances in breast cancer screening, diagnosis and management, the mortality has not changed much over the past several decades. Better understanding of the biology of breast cancer cells and the mechanism of how the cancer cells escape the body’s immune system is needed for any significant therapeutic improvements against breast cancer. We are working on a novel protein, heat shock protein 27 (hsp27) that is highly expressed inside breast cancer cells. We have preliminary data that some breast cancer cells secrete hsp27. We have also demonstrated that hsp27 can induce high levels of an anti-ininflammatory protein (known as interleukin-10; IL-10) in human monocytes. IL-10 can also suppress the immune system by inhibiting development of another type of immune cells called dendritic cells (DC). DCs are very important for the development of cytotoxic T lymphocytes (CTL) that are needed for killing the majority of cancer cells in the body. Recently, we found out that hsp27 can inhibit DC development. B. Objective/Hypothesis: We hypothesize that serum hsp27 levels are increased in breast cancer patients and inhibit DC development in breast cancer patients. Lack of functional DC may lead to defective development of CTLs in these patients. Such defective anti-tumor immune functions may eventually result in the faster progression of breast cancer. C. Specific Aims: We will evaluate whether the serum hsp27 level is a better prognostic marker for breast cancer. We will also test whether hsp27 can down-regulate immune functions in breast cancer. D. Study Design: Serum levels of CA 15-3 (a long-tested biomarker with fairly reliable sensitivity) and hsp27 will be simultaneously measured in patients’ serum during the course of the disease to test whether hsp27 is a better prognostic marker. Experiments to explore the inhibitory effect of hsp27 on the body’s immune functions against breast cancer will also be performed. E. Potential Outcomes and Benefits of the Research: Our proposal will reveal: 1) the possibility of using serum hsp27 levels as a better prognostic biomarker for breast cancer, which may be helpful in assessing the responses to different therapies, and 2) one of the mechanisms used by breast cancer cells to escape the body’s immune system that may help with designing a better strategy for developing treatments for breast cancer.