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    Research Grants Awarded

    Controlling Mammary Luminal And Basal Progenitor Cell Proliferation, Differentiation, And Tumorigenesis

    Grant Mechanism:
    Investigator Initiated Research

    Scientific Abstract:
    Breast cancer is heterogeneous, with tumors both pathologically distinct and diverse in their responsiveness to treatment. Gene expression profiling has categorized this complex disease into five clinically relevant subtypes, of which luminal A and basal-like tumors in particular are associated with distinct different gene expression patterns and clinical outcomes. Luminal A type tumors account for the majority (30 - 40%) of human breast cancers and generally have good relapse-free and overall survival, whereas basal-like tumors account for smaller portion (10 - 15%), but are of high histological grade, are more aggressive, and are often associated with a poor prognosis. The genetic basis and cellular pathways leading to the development of these two distinct types of tumors are not understood and are the focus of this research application. Germline mutation in the tumor suppressor BRCA1 contributes to about half of familial breast cancer. A major development over the past several years has been the recognition that breast tumors from BRCA1 carriers bear striking morphological, immunological, and molecular similarities to sporadic basal-like tumors. The cellular pathway and molecular mechanism underlying BRCA1?s function in selectively suppressing basal-like tumors and potential function in regulating luminal/basal cell lineage determination and/or differentiation are not clear. In addition to germline mutations, decreased BRCA1 expression and BRCA1 promoter methylation have also been observed in sporadic breast cancers with a high degree of heterogeneity. Whether decreased BRCA1 expression contributes to or is a consequence of the development of sporadic basal-like tumors remains controversial at present. These issues will be investigated by the research described in this application. In mammalian cells, the G1-S transition is controlled primarily by the RB pathway consisting of CDK inhibitors-cyclin/CDK-RB-E2Fs. Alterations of the RB pathway are frequent among human breast cancers and include oncogenic amplification and overexpression of cyclins D1 and E1, loss-of-function mutations of p16INK4a and RB1, and decreased expression of p27KIP1 and p18INK4c. We have recently found that deletion of p18Ink4c, a haploinsufficient tumor suppressor whose loss or reduction is associated with the development of multiple types of human cancers at high frequency, causes mice to develop mammary luminal tumors at near complete penetrance. We further demonstrate that p18 is repressed by the luminal lineage determinant GATA3, functions in restraining luminal progenitors, and that p18 gene expression is decreased in human luminal A-type tumors. Significantly, Brca1 heterozygosity transforms luminal tumors developed in p18 null mice into basal-like tumors. Based on these preliminary studies, we hypothesize that p18 plays a critical role in mediating the GATA3-pathway of luminal lineage commitment and differentiation by restraining luminal progenitor cell proliferation. We further propose that BRCA1 plays an important function in mammary stem or bi-potent progenitor cells. Loss or reduction of BRCA1 activity promotes premature senescence in the presence of an intact RB pathway but causes transdifferentiation into basal cells when the RB pathway is comprised, leading to aggressive and heterogeneous basal-type tumors. Taking advantages of the unparalleled and unprecedented opportunity of high incidence of luminal tumors in p18 null mice and their transformation into basal-like tumors by Brca1 heterozygosity, we propose a series of experiments combining genetic, cellular, biochemical, bioinformatic, and therapeutic approaches to test these two hypotheses.

    Lay Abstract:
    Among American women, breast cancer is the most common type of cancer and the second leading cause of cancer-related mortality. Breast cancer is heterogeneous, with tumors both pathologically distinct and diverse in their responsiveness to treatment. Gene expression profiling has categorized this complex disease into five clinically relevant subtypes. Of these, luminal A type tumors account for the majority (30 - 40%) of human breast cancers and generally have good relapse-free and overall survival, whereas basal-like tumors are of high histological grade, accounting for about 10-15% of total cases, are more aggressive, often associated with a poor prognosis and if separated from other types of breast cancer would represent the number four cause of cancer deaths among American women. The genetic basis and cellular pathways leading to the development of these two distinct types of tumors are not understood, bears significant clinical relevance as these two types tumors respond differently to treatments and possess different prognosis, and are the focus of this research application. Mutation in the tumor suppressor BRCA1 is associated with half of familial breast cancer. A major development over the past several years is the recognition that breast tumors from BRCA1 carriers bear striking similarities to sporadic basal-like tumors. In addition to germline mutations, decreased BRCA1 expression has also been observed in sporadic breast cancers with high degree of heterogeneity. These findings raise two critical issues: why germline mutation in BRCA1 specifically causes basal-like tumors? What is the significance of BRCA1 decrease in sporadic breast cancer? The research described in this application will investigate both issues. During our studies of p18INK4c, an inhibitor of cell proliferation and a tumor suppressor whose expression is inactivated or reduced in multiple types of human cancers, we discovered that nearly all female mice lacking p18Ink4c develop luminal type tumors and that p18INK4c expression is significantly reduced in human luminal type breast cancers. We further discovered that combined mutation in p18Ink4c and Brca1 transformed luminal tumors into basal-like tumors. Based on these preliminary studies, we hypothesize that p18 plays a critical role in suppressing luminal type tumors by restraining luminal progenitor cell proliferation. We further hypothesize that BRCA1 plays an important function in regulating mammary stem or progenitor cells and that BRCA1 mutations normally cause cell growth arrest, but promote transdifferentiation into basal cells when 18INK4c function is comprised, leading to aggressive and heterogeneous basal-type tumors. Taking advantage of the unparalleled opportunity of high incidence of luminal tumors in p18INK4c deleted mice and their transformation into basal-like tumors by Brca1 heterozygosity, we propose a series of experiments combining genetic, cellular, biochemical, and bioinformatic to test these two hypotheses. Our model of study will also allow the scientific community to better understand the role of BRCA1 in human familial and sporadic breast cancer. This investigation has the potential to contribute greatly to the understanding of the development of both the most common and the most aggressive forms of human breast cancer, which in the end should translate into more targeted and better therapies at the bedside. Once complete, the study will provide a solid mouse modeling tool to facilitate a more complete and comprehensive understanding of breast cancer and enhance the work of other researchers in both academics and industry. In addition to shedding new and much needed light onto unknown aspects of ongoing and future genetic, cellular, biochemical, bioinformatic, and therapeutic work in the field of breast cancer study, the research described in this application will be of significant value to the public community, in turn benefiting breast cancer patients' diagnosis, treatment, and survival.