African Americans are more likely to express a subtype of tumors that lack ER/PR and HER2 (HER2/neu) receptors (triple negative), and are more difficult to treat due to lack of target receptors. In addition, another subtype, the HER2 overexpressing tumors, irrespective of race or ethnicity have poor outcome. These women are more likely to become resistant to chemotherapy and have shorter disease-free survival and poor overall survival. Recent microarray analysis from our laboratory on trastuzumab treated HER2 positive cells revealed significant downregulation of a transcription factor belonging to the SNAIL family, SLUG. In addition, the SLUG mRNA had significantly increased in trastuzumab resistant cells. It is unclear as to what role SLUG plays In HER2 overexpressing cells. We speculate that its overexpression contributes to trastuzumab resistance. We hypothesize that the tumor cells with increased expression of SLUG will decrease their E-cadherin expression and induce epithelial to mesenchymal cell transitions (EMT). The EMT resulting from HER2 overexpressing breast tumor cells might induce differentiation of cancer stem cells, with HER2 signaling playing a key role In maintaining their self-renewal, proliferation, and Induction of cell metastases. Trastuzumab will downregulate SLUG, inhibit E-cadherin downregulation, inhibit EMT, and prevent cancer stem cell differentiation and tumor metastases. To test our hypotheses, we have proposed four specific aims in this application.
Specific Aim 1 will determine if the SLUG is deregulated in relation to activation of Akt (pAkt) and HER2 overexpression in breast cancer tissue and cell lines, as well as in primary mammary tissue cell lines undergoing EMT.
Specific Aim 2 will determine mechanisms by which increased expression of pAkt and HER2 lead to SLUG regulation.
Specific Aim 3 will examine the clinical correlation between tissue overexpression of HER2, and pAkt in relation to SLUG and its effect on disease-free and overall survival. The model to test our hypotheses will include 1) HER2 overexpressing breast cancer cell lines, SKBR3 and BT474;cells with moderate expression of HER2, MCF-7, and normal breast cell lines, MCF-10 and MCF12A obtained from ATCC;2) breast tumor tissue from African American and Latina patients and cell lines established from these tissues. The role of SLUG in cells undergoing EMT will be tested in the primary mammary tissue cultured cell lines. In addition the trastuzumab resistant cell lines and the HER2 overexpressing cells transfected with myr-Aktl will also be used.
Specific Aim 4 will develop a MMTV-rtTA/TetO-myr-Aktl transgenic mice model to study the regulation and functions of Akt in EMTs in normal mammary tissue and mammary tumors. The role of SLUG and SNAIL1 in the transition and progression of mammary tumors will be determined in Aim 4.The data gathered from this study will lead us to better understand the breast tumor pathogenesis, and help to design studies for future therapeutic intervention of tumor metastases and improve the disease-free survival of breast cancer patients.
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