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Regulation of SRC-3/AIB1 Function by Akt/PKB Kinase Signaling Pathway and the Potential Role in Endocrine Therapy Resistance
Tumor Cell Biology I
Scientific Abstract The gene for SRC-3 (also known as AIB1 for amplified in breast cancer-1) has been shown to be amplified in 10% of human breast tumors, and elevated SRC-3/AIB1 mRNA expression was found for 64% of tumors. Recently, SRC-3/AIB1 was shown to be a bona fide oncogene and plays an important role in mammary gland tumorigenesis in mouse model. Interestingly, the activity and function of SRC-3/AIB1 oncogene are regulated by phosphorylation. It is conceivable that abnormal activation of SRC-3/AIB1 by phosphorylation could bypass the normal regulatory mechanism and result in the development of diseases or difficulty for successful treatment for these diseases. In fact, increased phosphorylatioin, elevated levels of SRC-3/AIB1 and aberrant activation of kinase signaling pathways are all associated with tumorigeneis, resistance to hormone replacement therapy and poor survival of breast cancer patients. Although increasing body of evidence strongly supports phosphorylation as an important regulatory mechanism, the exact critical phosphorylation sites on SRC-3/AIB1 and the important kinases have not yet been identified. Recently, we identified six functionally important SRC-3/AIB1 phosphorylation sites by mass spectrometry. However, their potential roles in tumorigenesis and endocrine resistance remain unknown. In current study, we propose to invevstigate which SRC-3 phosphorylation sites are important for tumorigenesis and to identify the responsible kinases that phosphorylate SRC-3. Interestingly, our preliminary results identified Akt-GSK3 as one of the candidate kinase pathway that regulates the levels/stability of SRC-3 oncoprotien through phosphorylation of Ser505 on SRC-3. Since SRC-3 is an oncogene, elevated levels/stability of SRC-3 oncoprotein is of biological significane. Future study will aim at demonstrating the importance of Ser505 phosphorylation of SRC-3 in cancer cell proliferation and survival and elucidating the underlying mechanism. Collectively, this study will shed new light on the biological importance of SRC-3 phosphorylation and provide potential new understanding to endocrine resistance. Given the known importance of SRC-3 in breast cancer, these results will validate SRC-3 as a potential target for future medical intervention to better treat breast cancer.
Lay Abstract Breast cancer is the second leading cause of cancer related deaths for women in the United States. The genetic determinants for most breast cancer cases are still not entirely clear and the precise etiological pathways remain to be fully elucidated. However, a large body of evidence has demonstrated that hormones, such as estrogen and its receptor (estrogen receptor, ER), play critical roles in the pathogenesis of breast cancer by controlling the expression of numerous important cellular genes. Therefore, endocrine therapy directed at suppressing ER function is currently the most important systemic treatment of ER-positive breast cancer at all stages. However, resistance to various endocrine therapy is still a big problem that not only limits the application of this therapy but also leads to tumor progression and patient death. Therefore, understanding the underlying mechanism for endocrine resistance has become increasingly crucial for better treatment of breast cancer. The function of ER depends on another protein, SRC-3 (steroid receptor coactivator-3). SRC-3 (also known as AIB1 for amplified in breast cancer-1) is an oncogene (tumor causing gene) whose activity is regulated via phosphorylation (addition of phosphorus group) by cellular kinase signaling pathways (proteins that carry out the phosphorylation reaction). Interestingly, compelling evidence suggests that crosstalk between ER-SRC-3 and kinase signaling pathways plays a major role in the development of endocrine resistance. It is conceivable that activation of kinases could result in increased activation of SRC-3/AIB1 and the development of diseases or failure of treatment for such diseases. In fact, increased levels of SRC-3/AIB1 oncogene and aberrant kinase activities are frequently found in human cancers and are critical contributing factors to the failure for the treatment of breast cancer. To demonstrate the importance of SRC-3 phosphorylation for the development of endocrine resistance in breast cancer, we recently identified six SRC-3 phosphorylation sites. In this proposal, we propose to investigate which of these six SRC-3 phosphorylation sites are potentially important for the endocrine resistance and to identify the responsible kinases that phosphorylate SRC-3. Significantly, our preliminary results identified the important Akt-GSK3 as one of the candidate kinase pathway that regulates the levels/stability of SRC-3 oncoprotien through phosphorylation of one critical amino acid on SRC-3. We propose to substantiate the importance of SRC-3 phosphorylation by studying cancer cell growth and cell survival in response to various therapeutic agents. We believe that this study is clinically relevant to treatment of breast cancer and upon successful completion of this study our results could potentially lead to an improved treatment for breast cancer.