Abstract

Cancers arise and progress by a series of genetic and biochemical events that remain to be fully described. During the initial period of support for this project, we have characterized several mouse models of breast carcinoma by examining morphological features, lymph node dependence, their genotypes and expression phenotypes, and mechanisms of oncogenesis by Wnt signaling elements. We have also learned to deliver viral vectors to mammary and pancreatic islet cells and have confirmed the ability of two candidate genes to promote tumor progression in islet cells. In the new proposal, we continue to use a variety of mouse models of breast cancer and a model of islet cell carcinogenesis, plus three dimensional tissue culture methods and materials from stored human tumor samples, to explore several issues related to the molecular basis of neoplasia. Virus vectors will be used to assess many genes and micro-RNAs as contributors to tumor progression in the pancreatic and mammary cancer models. We will seek to understand the phenomenon of oncogene dependence by using conditional oncogenic transgenes and viral vectors to identify factors that protect tumors from oncogene-dependence. And we will explore our preliminary evidence that oncogenesis by components of Wnt signaling pathways is mediated by fibroblast growth factors or members of the protein kinase C (PKC) family.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA094060-10
Application #
8382391
Study Section
Special Emphasis Panel (ZCA1-RPRB-O)
Project Start
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
10
Fiscal Year
2012
Total Cost
$415,238
Indirect Cost
$196,231

  Institution

Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065

  Publications

Er, Ekrem Emrah; Valiente, Manuel; Ganesh, Karuna et al. (2018) Pericyte-like spreading by disseminated cancer cells activates YAP and MRTF for metastatic colonization. Nat Cell Biol 20:966-978
Chen, Chun-Chin; Kass, Elizabeth M; Yen, Wei-Feng et al. (2017) ATM loss leads to synthetic lethality in BRCA1 BRCT mutant mice associated with exacerbated defects in homology-directed repair. Proc Natl Acad Sci U S A 114:7665-7670
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
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
Chen, Qing; Boire, Adrienne; Jin, Xin et al. (2016) Carcinoma-astrocyte gap junctions promote brain metastasis by cGAMP transfer. Nature 533:493-498
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
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 :

Showing the most recent 10 out of 97 publications