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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA080111-14
Application #
8374823
Study Section
Special Emphasis Panel (ZCA1-GRB-S)
Project Start
Project End
Budget Start
2012-02-01
Budget End
2013-01-31
Support Year
14
Fiscal Year
2012
Total Cost
$306,512
Indirect Cost
$41,274
Name
Whitehead Institute for Biomedical Research
Department
Type
DUNS #
120989983
City
Cambridge
State
MA
Country
United States
Zip Code
02142
Zhang, Jinfang; Xu, Kai; Liu, Pengda et al. (2016) Inhibition of Rb Phosphorylation Leads to mTORC2-Mediated Activation of Akt. Mol Cell 62:929-42
Spiegel, Asaf; Brooks, Mary W; Houshyar, Samin et al. (2016) Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells. Cancer Discov 6:630-49
Shu, Shaokun; Lin, Charles Y; He, Housheng Hansen et al. (2016) Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer. Nature 529:413-7
Hydbring, Per; Malumbres, Marcos; Sicinski, Piotr (2016) Non-canonical functions of cell cycle cyclins and cyclin-dependent kinases. Nat Rev Mol Cell Biol 17:280-92
De Cock, Jasmine M; Shibue, Tsukasa; Dongre, Anushka et al. (2016) Inflammation Triggers Zeb1-Dependent Escape from Tumor Latency. Cancer Res 76:6778-6784
Malorni, Luca; Giuliano, Mario; Migliaccio, Ilenia et al. (2016) Blockade of AP-1 Potentiates Endocrine Therapy and Overcomes Resistance. Mol Cancer Res 14:470-81
Fu, Xiaoyong; Jeselsohn, Rinath; Pereira, Resel et al. (2016) FOXA1 overexpression mediates endocrine resistance by altering the ER transcriptome and IL-8 expression in ER-positive breast cancer. Proc Natl Acad Sci U S A 113:E6600-E6609
Huh, Sung Jin; Oh, Hannah; Peterson, Michael A et al. (2016) The Proliferative Activity of Mammary Epithelial Cells in Normal Tissue Predicts Breast Cancer Risk in Premenopausal Women. Cancer Res 76:1926-34
Wang, Hua; Bierie, Brian; Li, Andrew G et al. (2016) BRCA1/FANCD2/BRG1-Driven DNA Repair Stabilizes the Differentiation State of Human Mammary Epithelial Cells. Mol Cell 63:277-92
Goel, Shom; Wang, Qi; Watt, April C et al. (2016) Overcoming Therapeutic Resistance in HER2-Positive Breast Cancers with CDK4/6 Inhibitors. Cancer Cell 29:255-69

Showing the most recent 10 out of 114 publications