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Research Grants Awarded
Using Mouse Models to Define the Role of Cell Death in Mammary Gland Development and Breast Cancer Initiation.
The mammary gland undergoes a morphogenetic program during embryogenesis and puberty, which leads to the development of hollow ductal system terminating in acinar units. It later expands to generate an elaborate network to deliver milk to newborn progeny. A hallmark of early carcinogenesis is filling of the luminal space of acini and ducts. The mechanisms involved in remodeling of the mammary ducts during puberty are poorly understood. Similarly, the processes that mediate luminal filling during carcinogenesis remain uncharacterized. My research project will focus upon the in vivo analysis of the role of apoptosis during normal mammary gland development and breast cancer initiation. Previous studies in the Brugge laboratory using three-dimensional basement membrane cultures of mammary epithelial cells, in which acini-like structures form from single cells, have indicated that filling of the lumen requires escape from cell death processes. Normally, programmed cell death clears the lumen of aberrantly proliferating cells. These in vitro studies highlighted two program cell death processes in the morphogenesis of the acini and their lumen: apoptosis and autophagy. The first process is linked to a pro-death mediator BIM in the in vitro mammary acinar model. Strongly supported by these in vitro data, we will investigate the in vivo role of apoptosis during mammary morphogenesis and breast cancer initiation using molecular tools and transgenic mouse models (Bim-/-; Bim F/F and Mmtv-CCND1-T286A mouse lines). This mouse genetic approach is currently focused on the virgin adult ductal outgrowth (Bim-/- mouse line). In preliminary studies, we have found dramatic alterations in the development of the mammary gland during puberty, in 5-week-old Bim -/- mice . The lumen of terminal end buds and distal ducts is filled of epithelial cells. This important result suggests that BIM is necessary for lumen formation during pubertal outgrowth. Later, in mature virgin mammary gland, the Bim -/- mammary ducts are hollow and cleared by a non-apoptotic processes. Thus, the loss of Bim by itself does not seem to be sufficient either to support a long-term luminal filling or to initiate carcinogenesis. To investigate whether Bim could serve as a tumor suppressor, we will investigate cooperation between the loss of Bim mediated cell death and a proliferative oncogene, such as nuclear Cyclin D1, in mammary neoplastic transformation (Bim F/F and Mmtv-CCND1-T286A mouse lines). Cyclin D1 is a critical mediator of cell cycle progression during G1 phase. Cyclin D1 is found to be overexpressed in at least 50% of human primary breast cancers. These studies will reveal important information on the role of apoptosis in natural processes that are involved in ductal morphogenesis. This will be also valuable in understanding how oncogenes subvert this process during carcinogenesis.
The mammary gland undergoes a developmental program during embryogenesis and puberty, which leads to the creation of hollow branched system terminating in alveoli units. This network will later expand to deliver milk to newborn progeny. The hollow demarcated by mammary cells is also referred as the luminal space. In the Brugge laboratory, an in vitro cell culture system recapitulating mammary alveoli development in three-dimensional (acinus) indicated that invasion of the luminal space is following on loss of cell death capacity. Selective cell suicide (apoptosis) is crucial as examples for maintaining adult tissue integrity and sculpting the embryo. Disturbed regulation of this vital process underlies many diseases, including cancer. Thus, luminal filling is a hallmark of early stages of breast cancer development. My research project will focus upon the in vivo analysis of the role of selective cell suicide, during the development of mouse adult mammary gland and breast cancer initiation. The in vitro studies above highlighted BIM, a protein involved in programmed cell death processes. Strongly supported by these in vitro data, the in vivo function of programmed cell death is being investigated during mammary development with molecular tools and genetically modified mouse models. Indeed, cell death involvement in normal mammary gland formation is poorly understood. Our preliminary results indicate that the mammary gland development is deeply perturbed in mice genetically invalidated for Bim gene (Bim -/- mouse). During puberty, the lumen of Bim -/- mammary ducts is filled of cells. Indeed, the selective cell suicide of the inner cells necessary for lumen formation does not seem to occur in the Bim -/- mammary glands. Nevertheless, at the end of puberty, the Bim -/- mammary ducts are hollowed by a non-selective death process. Thus, even though Bim is important during the pubertal development, the loss of Bim-mediated cell death alone does not trigger tumor development in the lumen of mammary ducts. To examine whether loss of Bim promotes tumor development in the context of other oncogenes, we will investigate if combination of the loss of Bim mediated cell death and an oncogene, such as Cyclin D1 protein, can synergize breast tumor development. The Cyclin D1 protein is a critical mediator of cell proliferation. In addition, Cyclin D1 is found to be overexpressed in at least 50% of human primary breast cancers. These studies will reveal important information on the natural processes that are involved in luminal space formation. This will be valuable in understanding how promoting tumor factors subvert this process during cancer development. Interfering with such tumor factors-induced processes represents an attractive strategy to induce death of tumor cells.