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The Role of Six1, and its Target Cyclin A1, in Breast Cancer
During development, many changes take place that parallel those seen in cancer. Homeobox genes are implicated in numerous processes during development, and are often altered in cancer. The Six1 homeobox gene is overexpressed in 44% of primary breast cancers and 90% of metastatic lesions. Recently, Six1 was shown to be critical for the proliferation and survival of progenitor cells prior to differentiation. Six1 has also been shown play a role in proliferation and in the DNA damage-induced G2 checkpoint in breast cancer cells. We are interested in the molecular mechanism by which Six1, when aberrantly expressed, promotes breast cancer. We recently demonstrated that Six1 regulates the transcription of the germ-line/embryonic-specific cyclin A1, and suggest that activation of cyclin A1 can promote an embryonic pathway for proliferation in breast cancer. Hypothesis: Six1 overexpression results in the acquisition of properties normally conveyed on a developing cell. The increased proliferation observed with Six1 overexpression is the result of activation of a germ line/embryonic-specific cyclin A1, which normally acts in development. Expression of Cyclin A1 as a consequence of Six1 overexpression directly contributes to breast tumorigenesis by promoting proliferation out of context. Aims:(1) To determine whether Cyclin A1 is a relevant target of Six1 in mediating its effects on breast cancer (2) To examine the function of Six1 and cyclin A1 in mammary tumorigenesis using a transgenic mouse model system. Study Design: In the first aim, we will dissect the relevance of a target of Six1, Cyclin A1, in breast cancer. This will be done by assessing whether phenotypes conferred by Six1 act through Cyclin A1, and by determining whether Six1, Cyclin A1, and proliferation correlate in breast tumors. In the second aim we will utilize an inducible mammary specific Six1 mouse model system to ask whether Six1 overexpression in the mammary gland can lead to cancer. To test the dependence of Six1 on cyclin A1, we will cross our Six1 transgenic mice with cyclin A1 knockout mice. This study will provide us with information as to how genes important in normal development can be “hijacked” to perform tumor promoting functions later in life. The link between development and cancer is critical, particularly as some developmental genes that are overexpressed in cancer, but absent or very low in noncancerous adult cells, may serve as ideal drug targets as long as development is complete at the time the cancer arises. Six1 may be such an ideal target for breast cancer treatment.
Background: Normal Development and tumorigenesis share many properties. Among these are changes in cell growth (proliferation), in migration, in invasion, and in vascularization. Our laboratory is interested in a family of genes (the Six family) that are important in normal development and are improperly regulated in cancer. The improper regulation of these genes may thus impart properties on the adult cell that are normally found in developing cells; properties such as increased proliferation, migration, or invasion, all which could contribute to tumorigenesis. One of the Six family members, Six1, is overexpressed in almost 50% of primary breast tumors and 90% of metastatic lesions. Six1 is involved in the proliferation that is required during development, and we have shown that its misexpression in breast cancer cells can lead to uncontrolled growth, a hallmark of cancer. The Six1 gene encodes a transcription factor, a protein that regulates the expression of many other genes. We have recently discovered that Six1 regulates the expression of a germ-line and embryonic specific cyclin, cyclin A1, which is known to control the cell cycle during normal development. Hypothesis: We propose that Six1 influences breast tumorigenesis by activating cyclin A1, and that this sets in motion an embryonic pathway for proliferation in the adult that results in cancer. Specific Aims/Study Design: In this proposal, we would like to determine how Six1 affects breast tumorigenesis, both at the cellular and molecular level using cell culture and mouse model systems. We would further like to determine whether activation of cyclin A1 is critical for the role of Six1 in breast tumorigenesis. Benefits of Research: The link between normal development and tumorigenesis is critical and deserves much attention for the following reason: Genes that are critical during normal development, are no longer needed in the adult cell, but are re-expressed in tumors could be excellent drug targets provided that development is complete at the time the tumor arises. Thus, understanding the mechanism of action of Six1 in breast tumorigenesis may provide us with insight into developing rational drug therapies against the gene itself or against genes in its pathway.