The goal of this project is to define the molecular function of cyclin D1 in mammary gland development and n breast cancer. Cyclin D1 is a component of the core cell cycle machinery. The best-documented function of cyclin D1 is its ability to bind and to activate the cyclin-dependent kinases CDK4 and CDK6. In addition, cyclin D1 was proposed to play CDK-independent, possibly cell cycle-independent functions by acting as a :o-activa1or or -represser of specific transcription factors. The cyclin D1 gene is amplified in 15-20% of uiman mammary carcinomas, whereas cyclin D1 protein is overexpressedin the majority of human breast cancers. In the past, we used cyclin D1 knockout and knock-in mice to demonstrate the requirement for cyclin D1 function in normal breast development and in breast neoplasia. The exact molecular function of cyclin D1 in these processes is currently unclear. The goal of this proposal is to elucidate the full range of cyclin D1's molecular functions in normal breast development, and in mammary tumorigenesis. To address this issue, we recently generated a novel knock-in strain of mice expressing tandemly-tagged version of cyclin D1. This strain allows us to use sequential immunoaffinity purifications followed by high-sensitivity shot-gun mass spec sequencing to define the full range of cyclin D1 interacting partners in essentially any organ, at any point of development, and at any stage of cancer progression. We have already demonstrated that this general approach is successful, and we will now apply it to analyses of mammary glands and mammary carcinomas. We will combine our analyses with studies of human breast cancers. The combined use of these approaches will allow us to determine the molecular functions of cyclin D1 in normal breast development, and will help to understand how these functions are deranged in breast neoplasia.
The Specific Aims are:
Aim 1 : To study the molecular function of cyclin D1 during mammary development.
Aim 2 : To study the molecular function of cyclin D1 during mammary neoplasia.
TO PUBLIC HEALTH Cyclin D1 protein is overexpressed in many human cancers, including the majority of breast cancers. Although the key role for cyclin D1 overexpression in pathogenesis of mammary carcinomas is firmly established, the exact molecular function of cyclin D1 in this process remains unclear. The work proposed in this application will address this critical issue. Understanding of cyclin D1's function in neoplasia is essential in order to design rational therapeutic strategies.
|Rashidian, Mohammad; Ingram, Jessica R; Dougan, Michael et al. (2017) Predicting the response to CTLA-4 blockade by longitudinal noninvasive monitoring of CD8 T cells. J Exp Med 214:2243-2255|
|Dreijerink, Koen M A; Timmers, H T Marc; Brown, Myles (2017) Twenty years of menin: emerging opportunities for restoration of transcriptional regulation in MEN1. Endocr Relat Cancer 24:T135-T145|
|Hydbring, Per; Wang, Yinan; Fassl, Anne et al. (2017) Cell-Cycle-Targeting MicroRNAs as Therapeutic Tools against Refractory Cancers. Cancer Cell 31:576-590.e8|
|Bierie, Brian; Pierce, Sarah E; Kroeger, Cornelia et al. (2017) Integrin-?4 identifies cancer stem cell-enriched populations of partially mesenchymal carcinoma cells. Proc Natl Acad Sci U S A 114:E2337-E2346|
|Wang, Yu; Woehrstein, Johannes B; Donoghue, Noah et al. (2017) Rapid Sequential in Situ Multiplexing with DNA Exchange Imaging in Neuronal Cells and Tissues. Nano Lett 17:6131-6139|
|Dongre, Anushka; Rashidian, Mohammad; Reinhardt, Ferenc et al. (2017) Epithelial-to-Mesenchymal Transition Contributes to Immunosuppression in Breast Carcinomas. Cancer Res 77:3982-3989|
|Dreijerink, Koen M A; Groner, Anna C; Vos, Erica S M et al. (2017) Enhancer-Mediated Oncogenic Function of the Menin Tumor Suppressor in Breast Cancer. Cell Rep 18:2359-2372|
|Wang, Haizhen; Nicolay, Brandon N; Chick, Joel M et al. (2017) The metabolic function of cyclin D3-CDK6 kinase in cancer cell survival. Nature 546:426-430|
|Hydbring, Per; Wang, Yinan; Bogorad, Roman L et al. (2017) Identification of cell cycle-targeting microRNAs through genome-wide screens. Cell Cycle 16:2241-2248|
|Tavera-Mendoza, Luz E; Westerling, Thomas; Libby, Eric et al. (2017) Vitamin D receptor regulates autophagy in the normal mammary gland and in luminal breast cancer cells. Proc Natl Acad Sci U S A 114:E2186-E2194|
Showing the most recent 10 out of 127 publications