Abstract

Breast Cancer is a leading cause of cancer death in the United States with ~200,000 new cases and ~40,000 deaths each year. A better understanding of the genetic effectors of tumor growth and suppression would enable the identification of new targets for therapy.
The aims of this proposal are directed at identifying and validating key components of the TGF-beta signaling pathway that would lead to the development of specific therapies for the treatment of breast cancer.
AIM 1 : Analyzingthe role of cdc25A in TGF-beta mediated growth stimulation of breast epithelial cells. Our initial studies demonstrated that TGF- beta mediated growth stimulation correlated with an increased expression of the cdc25A tyrosine phosphatase gene in cells lacking p21. In this aim we will further analyze the ability of cdc25A to mediate TGF-beta induced cellular proliferation using RNA interference, promoter/mutational/ChIP assays, and p21 cDNA mutational studies, coupled with an analysis of human breast cancers using tissue microarrays.
AIM 2 : Identifying mediators of TGF-beta induced cellular proliferation.
In Aim 2, we hypothesize that there are other integral genes whose upregulation is needed for TGF-beta induced growth stimulation. We will use microarray expression analysis to identify these genes using our previously characterized p21-/- cell lines. In order to validate that these genes are true mediators of TGF-beta stimulated cellular proliferation, RNA interference gene """"""""knock down"""""""" experiments and targeted gene ablation via homologous recombination will be performed.
AIM 3 : Identifying genetic effectorsthat mediate the growth response to TGF-beta. In this aim, we will identify additional effectors of TGF-beta mediated growth inhibition using a functional genetic screen. We will combine exon trapping with genetic instability to isolate genes whose inactivation confers resistance to TGF-beta mediated growth suppression. Isolated genes will be verified and validated by restoration of the putative gene and correlated with immunohistochemical studies using tissue microarrays.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA109274-04
Application #
7535591
Study Section
Tumor Cell Biology Study Section (TCB)
Program Officer
Ault, Grace S
Project Start
2006-02-01
Project End
2010-12-31
Budget Start
2009-01-01
Budget End
2009-12-31
Support Year
4
Fiscal Year
2009
Total Cost
$254,392
Indirect Cost

  Institution

Name
Johns Hopkins University
Department
Other Health Professions
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218

  Publications

Cochran, Rory L; Cravero, Karen; Chu, David et al. (2014) Analysis of BRCA2 loss of heterozygosity in tumor tissue using droplet digital polymerase chain reaction. Hum Pathol 45:1546-1550
Beaver, Julia A; Jelovac, Danijela; Balukrishna, Sasidharan et al. (2014) Detection of cancer DNA in plasma of patients with early-stage breast cancer. Clin Cancer Res 20:2643-2650
Wang, Grace M; Wong, Hong Yuen; Konishi, Hiroyuki et al. (2013) Single copies of mutant KRAS and mutant PIK3CA cooperate in immortalized human epithelial cells to induce tumor formation. Cancer Res 73:3248-61
Higgins, Michaela J; Jelovac, Danijela; Barnathan, Evan et al. (2012) Detection of tumor PIK3CA status in metastatic breast cancer using peripheral blood. Clin Cancer Res 18:3462-9
Garay, Joseph P; Park, Ben H (2012) Androgen receptor as a targeted therapy for breast cancer. Am J Cancer Res 2:434-45
Garay, Joseph P; Karakas, Bedri; Abukhdeir, Abde M et al. (2012) The growth response to androgen receptor signaling in ERýý-negative human breast cells is dependent on p21 and mediated by MAPK activation. Breast Cancer Res 14:R27
Cidado, Justin; Park, Ben Ho (2012) Targeting the PI3K/Akt/mTOR pathway for breast cancer therapy. J Mammary Gland Biol Neoplasia 17:205-16
Beaver, Julia A; Park, Ben H (2012) The BOLERO-2 trial: the addition of everolimus to exemestane in the treatment of postmenopausal hormone receptor-positive advanced breast cancer. Future Oncol 8:651-7
Lauring, Josh; Park, Ben Ho (2011) BEAMing sheds light on drug resistance. Clin Cancer Res 17:7508-10
Higgins, Michaela J; Beaver, Julia A; Wong, Hong Yuen et al. (2011) PIK3CA mutations and EGFR overexpression predict for lithium sensitivity in human breast epithelial cells. Cancer Biol Ther 11:358-67

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