This Program Project Grant application presents five interactive laboratory projects and two cores dedicated to making progress against human breast cancer by studying mouse models. It achieves synergy and an economy of effort by sharing existing strains, collaboratively developing new strains, designing and using an Imaging Core, discovering and applying new methods for genotyping and phenotyping, and the execution of therapeutic trials in mice using P01-developed reagents. Active cancer clinicians in the P01 are committed to assuring a meaningful impact on clinical thinking, education, and research. Project 1 focuses on the genes implicated in mammary cancer formation and progression, applying avian retroviral vector-based delivery of genes to mammary cells in vivo and iin vitro. Project 2 delineates the effects of the loss of TGF.'s tumor-suppressive function in metastatic breast cancer cells and studies a lung metastasis gene expression signature, including Id genes, that mediates pulmonary metastasis in mouse and human. Project 3 will use Hsp90 inhibitors and selective inhibitors of PI3K and AKt to determine the role of PI3K/AKt signaling in cancer, and continue to explore joint Hsp90 and HER2 modulation, which has already led to a clinical advance. Project 4 will characterize mammary tumors and their lung metastases occurring in HDR-deficient mammary epithelium. It will evaluate genetic instability in diverse mouse models to define the DNA damage response in normal, repair-deficient and oncogene-induced mammary epithelium. Project 5 will examine the effects on tumor initiation, progression, and metastasis of conditional Id-family over-expression in murine mammary epithelial cells and cancer epithelial cells arising from several well-defined genetic backgrounds. In collaboration with other projects it will examine the tumor-initiating and metastatic properties of Id1-variant models, and continue to develop therapeutic agents. The Imaging Core supplies advanced imaging technology to these projects. Larry Norton and Joan Massague serve as Program Director and Co-Director, and a Leadership Core will offer expertise in molecular array technology and biostatistics.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA094060-10
Application #
8323083
Study Section
Special Emphasis Panel (ZCA1-RPRB-O (J1))
Program Officer
Mohla, Suresh
Project Start
2002-09-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$2,914,689
Indirect Cost
$1,377,406
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065
Chen, Qing; Boire, Adrienne; Jin, Xin et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493-8
Kass, Elizabeth M; Lim, Pei Xin; Helgadottir, Hildur R et al. (2016) Robust homology-directed repair within mouse mammary tissue is not specifically affected by Brca2 mutation. Nat Commun 7:13241
Gao, Hua; Chakraborty, Goutam; Zhang, Zhanguo et al. (2016) Multi-organ Site Metastatic Reactivation Mediated by Non-canonical Discoidin Domain Receptor 1 Signaling. Cell 166:47-62
Ebbesen, Saya H; Scaltriti, Maurizio; Bialucha, Carl U et al. (2016) Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas. Proc Natl Acad Sci U S A 113:3030-5
Malladi, Srinivas; Macalinao, Danilo G; Jin, Xin et al. (2016) Metastatic Latency and Immune Evasion through Autocrine Inhibition of WNT. Cell 165:45-60
She, Qing-Bai; Gruvberger-Saal, Sofia K; Maurer, Matthew et al. (2016) Integrated molecular pathway analysis informs a synergistic combination therapy targeting PTEN/PI3K and EGFR pathways for basal-like breast cancer. BMC Cancer 16:587
Yang, C; Li, Z; Bhatt, T et al. (2016) Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence. Oncogene :
Rodrik-Outmezguine, Vanessa S; Okaniwa, Masanori; Yao, Zhan et al. (2016) Overcoming mTOR resistance mutations with a new-generation mTOR inhibitor. Nature 534:272-6
Obenauf, Anna C; Zou, Yilong; Ji, Andrew L et al. (2015) Therapy-induced tumour secretomes promote resistance and tumour progression. Nature 520:368-72
Okada, Tomoyo; Sinha, Surajit; Esposito, Ilaria et al. (2015) The Rho GTPase Rnd1 suppresses mammary tumorigenesis and EMT by restraining Ras-MAPK signalling. Nat Cell Biol 17:81-94

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