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.

Public Health Relevance

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.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Whitehead Institute for Biomedical Research
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Bailey, Shannon T; Westerling, Thomas; Brown, Myles (2015) Loss of estrogen-regulated microRNA expression increases HER2 signaling and is prognostic of poor outcome in luminal breast cancer. Cancer Res 75:436-45
Hines, William C; Su, Ying; Kuhn, Irene et al. (2014) Sorting out the FACS: a devil in the details. Cell Rep 6:779-81
Yamamoto, Shoji; Wu, Zhenhua; Russnes, Hege G et al. (2014) JARID1B is a luminal lineage-driving oncogene in breast cancer. Cancer Cell 25:762-77
Jeselsohn, Rinath; Yelensky, Roman; Buchwalter, Gilles et al. (2014) Emergence of constitutively active estrogen receptor-? mutations in pretreated advanced estrogen receptor-positive breast cancer. Clin Cancer Res 20:1757-67
Lu, Haihui; Clauser, Karl R; Tam, Wai Leong et al. (2014) A breast cancer stem cell niche supported by juxtacrine signalling from monocytes and macrophages. Nat Cell Biol 16:1105-17
Pathania, Shailja; Bade, Sangeeta; Le Guillou, Morwenna et al. (2014) BRCA1 haploinsufficiency for replication stress suppression in primary cells. Nat Commun 5:5496
Hu, Yiduo; Petit, Sarah A; Ficarro, Scott B et al. (2014) PARP1-driven poly-ADP-ribosylation regulates BRCA1 function in homologous recombination-mediated DNA repair. Cancer Discov 4:1430-47
McAllister, Sandra S; Weinberg, Robert A (2014) The tumour-induced systemic environment as a critical regulator of cancer progression and metastasis. Nat Cell Biol 16:717-27
Hill, Sarah J; Rolland, Thomas; Adelmant, Guillaume et al. (2014) Systematic screening reveals a role for BRCA1 in the response to transcription-associated DNA damage. Genes Dev 28:1957-75
Hill, Sarah J; Clark, Allison P; Silver, Daniel P et al. (2014) BRCA1 pathway function in basal-like breast cancer cells. Mol Cell Biol 34:3828-42

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