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    Research Grants Awarded

    Contribution of CUTL-1 to Basal Phenotype Breast Cancers

    Study Section:
    Postdoctoral Fellowship

    Scientific Abstract:
    The major goal of this proposal is to define the roles of a homeobox gene, CUTL-1, in basal phenotype breast cancers, which are highly aggressive breast tumors that lack expression of the estrogen receptor (ER), progesterone receptor (PR) and Her-2 making them refractory to Tamoxifen and Herceptin therapy. Moreover, they maintain expression of the basal epithelial markers cytokeratin 5 and a6ß4 integrin. CUTL-1 regulates organogenesis through transcriptional repression of cyclin-dependent kinase inhibitors and it has been linked to the behavior of aggressive breast tumors. Given that CUTL1 is linked to the expression of a6 integrins and the likely contribution of the a6ß4 integrin to the aggressive behavior of basal tumors, we hypothesize that CUTL1 expression is induced in basal tumors, that it contributes to their aggressive behavior and that it sustains expression of a6ß4, which is a potential therapeutic target for these tumors. Of interest, most, if not all basal breast tumors harbor inactivating mutations in BRCA1. Given that CUTL1 expression is repressed in basal epithelial cells, we hypothesize that mutational inactivation of BRCA1 facilitates CUTL1 expression. What emerges from this analysis is the central hypothesis that BRCA1 impedes CUTL1 in basal cells and that CUTL1 is essential for the aggressive behavior of BRCA1 mutant basal tumors. To address this hypothesis, we will: 1). Define the contribution of CUTL1 to the aggressive behavior of basal phenotype breast tumors. This aim will be accomplished by assessing CUTL1 expression in basal tumors, which will be identified by their ER/PR/Her-2 status and expression of cytokeratin-5. Also, CUTL1 expression will be depleted by RNAi in breast tumor cells that exhibit a basal phenotype and the ability of such cells to express a6ß4, as well as to form tumors, invade and metastasize will be examined. 2). Define the relationship between CUTL1 and BRCA1 in basal phenotype breast tumors. This aim will be accomplished by determining whether genetic inactivation of BRCA1 in normal basal epithelial cells induces CUTL1 expression and whether expression of wild-type BRCA1 in basal tumor cells represses CUTL1 expression. Importantly, we will also examine the hypothesis that forced expression of CUTL1 in cytokeratin 5-positive basal epithelial cells promotes mammary tumorigenesis and assess the contribution of BRCA1 to this tumorigenesis. Currently, there are no therapies that target basal tumors. The proposed studies will increase our understanding of why these tumors are so aggressive and validate two potential therapeutic targets: CUTL1 and a6ß4 integrin. These studies will also provide a novel link between CUTL1 and BRCA1 mutations, which are a primary cause of hereditary breast cancer.

    Lay Abstract:
    Although pathologists have developed a comprehensive classification of breast cancer based on tumor morphology, molecular profiling is providing new insight into nature and behavior of breast tumors. This approach has identified a population of tumors that are derived from the basal epithelial cells in the breast. These tumors, which account for 15-30% of all breast tumors, are highly aggressive and patients with such tumors have a poor prognosis. Interestingly, most tumors that are caused by mutations in the BRCA1 gene, which is linked to hereditary breast cancer, are of the basal type. Unfortunately, these tumors cannot be treated with Tamoxifen or Herceptin because they lack expression of the estrogen receptor and Her-2, and no therapies exist currently that target basal tumors specifically. This proposal will test the hypothesis that a specific protein, which is known to be expressed in high grade breast tumors, is responsible for the aggressive behavior of basal tumors and that this protein is a target for therapy in these tumors. This protein, CUTL-1, has the potential to control the expression of other molecules that can facilitate breast tumor spread. To address our hypothesis, we will assess the expression of CUTL-1 in women with basal tumors and we will determine whether this protein is responsible for the aggressive behavior of these tumors. We will also determine whether there is a link between inactivation of the BRCA1 gene and expression of CUTL-1. We will also test the possibility that expression of CUTL-1 in normal basal cells in the breast can promote the formation of tumors. We anticipate that the proposed studies will result in a much better understanding of these highly aggressive tumors and provide us with new markers and therapeutic targets.