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Functional Roles of HOXB7 in Tumorigenesis and Metastasis of Mammary Carcinoma
Background: Homeobox genes are regulatory genes encoding nuclear proteins that act as transcription factors during normal development and differentiation. The HOXB7 protein is involved in a variety of developmental processes, including hematopoietic differentiation and lymphoid and mammary gland development. Inappropriate expression of HOXB7 mRNA has been associated with breast cancer. Our Q-RT-PCR data has shown that HOXB7 genes is overexpressed in more than 60% breast cancer cell lines and 90% primary breast carcinomas. Further, microarray analysis of microdissected epithelial breast cancer cells revealed that HOXB7 is more than 10-fold overexpressed in bone metastasis compared to primary cancers. HOXB7 is oncogenic to breast epithelial cells-ectopic expression of HOXB7 transforms immortalized human mammary epithelial cells, MCF10A to form colonies in agar. The levels of EGF receptor and PDGF receptor beta, both of which are the important clinical breast cancer markers, dramatically increased in the cells as a result of HOXB7 expression. Clearly, further mechanistic studies are needed to investigate the role of HOXB7 in oncogenic transformation and metastasis in breast cancer.
Objective/Hypothesis: We hypothesize that overexpression of HOXB7 promotes breast tumorigenesis and bone-specific metastasis through one or more key signaling pathways, such as via the EGF receptor and PDGF receptor beta. Abrogation of HOXB7 expression will reverse the oncogenic phenotype of breast cancer cells via the reduction of the levels of overexpressed multiple receptor tyrosine kinases at the primary and distant metastatic sites.
The objective of this proposal is to gain an understanding of HOXB7 function by addressing the role of HOXB7 in tumorigenesis and metastasis, and further utilize it as a detection marker and rational therapeutic target of breast cancer. Specific Aims: (1) delineate the pathway of HOXB7 regulation of oncogenic signaling through EGFR and PDGF receptor-beta, 2) investigate the role of HOXB7 in bone specific metastasis in animal models, 3) develop an ELISA assay for presence of HOXB7 protein in the nipple aspirate fluid from cancer and high risk breast cases. These studies will lay the groundwork for future studies for developing HOXB7 as an early detection marker and for targeted drug development for breast cancer.
Potential Outcomes and Benefits of the Research: Identification of the mechanism of HOXB7 promoted breast tumorigenesis might reveal some underlying common mechanism shared by different types of breast tumor cells for overexpression of multiple receptor tyrosine kinases in breast carcinoma. The investigation of possible role of HOXB7 in metastasis of primary breast tumor cells to bone will give us an insight into the mechanism by which bone specific metastasis occurs. This information will be undoubtedly used for early diagnosis of aggressive primary tumors and for future therapeutic targeting. As well, knowledge gained here will contribute to a broader comprehension of the role of HOX genes in both breast cancer and many other cancers.
Breast cancer is a common disease that can be cured successfully by surgery or local irradiation if detected early or by preventing its spread to other organs by a process called metastasis. Thus it is important to determine the molecular processes by which a tumor cell starts to form in breast and moves from the breast to bone and other organs, causing a painful and debilitating condition. Recent results from our laboratory have revealed the presence of abnormally high levels of a protein known as HOXB7 in more than 90 percent of primary breast cancers, suggesting that this is a common and early event in the initiation of most of these tumors. Further analysis of bone metastasis tissue by microarray analysis study has shown that the breast carcinoma cells at that site also overexpress HOXB7 messenger RNA. Understanding the details of how tumors form, grow and metastasize, and how HOXB7 may be involved in these processes, is a very important issue in cancer biology that needs to be addressed in order to better treat the disease. The studies proposed here are designed to aid our understanding of how HOXB7 is involved in human breast cancer. In the proposed experiments, I will determine (1) the role of HOXB7 in regulating key genes such as receptors for epidermal growth factor and platelet-derived growth factor-beta and their downstream genes in breast cancer cells (2) understand the role of HOXB7 in promoting bone specific metastasis by injecting breast cancer cells engineered to overexpress HOXB7 and luciferase genes in mice and monitoring them for formation of bone metastasis by using imaging techniques. (3) develop a HOXB7 protein based approach for breast cancer early detection from women with high risk of developing breast cancer. This work will not only provide new insights into the development of breast tumors, but also has the potential to provide novel method of breast cancer early detection and improved models for the therapeutic treatment of breast cancer.