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Evaluating the Role of GKLF/KLF4 in Mammary Gland Development and Carcinogenesis
Tumor Cell Biology V
BACKGROUND: This proposal focuses on the role of Gut-enriched Kr ü ppel-like Factor (GKLF/KLF4), a member of the Kr üppel-Like Factor (KLF) family of transcription factors, in mammary gland development and carcinogenesis. While numerous studies have shown that GKLF acts as a tumor suppressor in colon, this protein may have opposite functions in breast. To date, only three studies have been reported regarding GKLF in the mammary gland. Breast cancers express GKLF and nuclear content of this protein increases with increasing aggressiveness. We have recently found that GKLF expression is induced with heregulin treatment of MCF-7 cells and that GKLF is expressed in breast cancers with HER2/neu amplification. These data are consistent with the notion that GKLF may promote growth and tumorigenesis of the mammary gland. OBJECTIVE/HYPOTHESIS: Given the high level of expression in aggressive breast cancers and the induction of GKLF by heregulin, we hypothesize that GKLF stimulates growth and tumorigenesis of the mammary gland. SPECIFIC AIMS/STUDY DEsign: We propose three specific aims to test the above hypothesis. Specific Aim 1: Determine if GKLF is necessary for normal mammary gland development. This study will take advantage of previously described GKLF knock-out mice. Since these mice die shortly after birth, we will use mammary gland transplantion techniques to determine if development of the gland is intrinsically altered with loss of GKLF. Specific Aim 2: Determine if GKLF overexpression causes mammary cancer. We will produce transgenic mice that overexpress GKLF in their mammary glands using the MMTV promoter. We will then determine if these mice have mammary gland defects and if they develop spontaneous mammary tumors with age. Specific Aim 3: Determine if GKLF overexpression accelerates development of HER2/neu-induced mammary tumors. We will breed mice from Aim 2 with the MMTV-c-neu model of breast cancer to determine if GKLF expression accelerates development of HER2/neu-induced tumors or if it changes metastatic progression of the tumors arising in these mice. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: The experiments proposed will be the first to directly assess the role of GKLF in mammary gland growth, development, and tumorigenesis. If GKLF induces or promotes tumorigenesis, these data would support its use as a target for developing chemopreventatives and chemotherapeutics.
BACKGROUND: Changes in gene activity can promote or inhibit carcinogenesis. Such changes are regulated by proteins known as transcription factors. This proposal focuses on a specific transcription factor known as Gut-enriched Kr ü ppel-like factor (GKLF/KLF4). In colon, GKLF inhibits development of tumors. Colon carcinomas acquire multiple mechanisms for losing GKLF protein, indicating that GKLF can act as a tumor suppressor. While it is tempting to speculate that GKLF would have tumor inhibitory properties in all cell types, this does not appear to be true. In particular, GKLF is actually increased in breast cancer, with more aggressive cancers having the highest levels of GKLF within their nuclei. This increase in nuclear content of GKLF suggests that it is regulating target genes in breast cancer. Hence, GKLF may actually be a tumor-inducing agent in breast. Remarkably, only three reports exist examining GKLF in breast, limiting our knowledge about its function in breast cancer. We recently observed increased GKLF expression in response to HER2/neu activation and observed GKLF expression in HER2/neu positive breast cancers. Thus, we suggest that GKLF may be an important regulator of mammary gland growth and may be an intermediate in HER2/neu-induced breast cancer. OBJECTIVE/HYPOTHESIS: We hypothesize that GKLF stimulates breast growth and tumor development. SPECIFIC AIMS/STUDY DESIGN: Specific Aim 1: Determine if GKLF is necessary for normal mammary gland development. We will use mice lacking an intact copy of the GKLF gene. These mice die shortly after birth, thus we will use mammary gland transplantation to determine if development of the gland is altered with loss of GKLF. Specific Aim 2: Determine if GKLF overexpression causes mammary cancer. We will produce transgenic mice that overexpress GKLF in their mammary glands and determine if these mice develop mammary tumors with age. Specific Aim 3: Determine if GKLF overexpression accelerates development of HER2/neu-induced mammary tumors. We will breed mice from Aim 2 with a well established model of HER2-amplified breast cancer and determine if GKLF overexpression enhances tumor development. POTENTIAL OUTCOMES AND BENEFITS OF THE RESEARCH: The experiments proposed will directly determine if GKLF regulates mammary gland growth and tumor formation. If so, this would suggest that GKLF may be an important target for future development of chemopreventatives and therapeutics.