Breast cancers overexpressing HER2/Neu do not respond to anti-hormone therapy and are more aggressive than their non-expressing counterparts. While the use of Herceptin, a humanized monoclonal antibody to HER2/Neu results in significant clinical response, many patients have intrinsic resistance or are expected to develop resistance to this therapy. Understanding the mechanisms by which HER2/Neu induces tumors and regulates their aggressiveness will be critical for developing more effective therapeutics. In this proposal, we describe three aims using cell-based assays and an in vivo transgenic mouse model that are geared towards identifying the regulatory circuitry initiated by HER2/Neu that is ultimately manifest in the formation of aggressive mammary cancer. We will examine three major regulatory components of tumors including the tumor/stroma interface, intracellular signaling targets of HER2/Neu, and a transcriptional nodal point. Regarding the tumor/stroma interface, we found that TGF-(5 signaling is suppressed early during tumorigenic progression due to loss of T-3RI. In contrast, stromally-derived activin appears to activate Smad2 within the tumor periphery, and activin promotes migration of isolated tumor cells. In this proposal, we will determine if activin signaling regulates tumorigenic progression. With regard to intracellular signaling intermediates, we found that rapamycin, an inhibitor of mTOR, causes regression of HER2/Neu tumors without inducing apoptosis or vascular collapse. We will now determine if rapamycin induces excessive autophagy in tumor cells and if tumors rely on a basal level of autophagy for survival. We will also determine if rapamycin regulates metastasis of HER2/Neu tumors and if anti-HER2 antibody therapy potentiates the efficacy of rapamycin. Lastly, we will focus on a transcription regulator, LMO4, which is an intermediate between HER2/Neu and cyclin D1 in breast cancer cells. We will determine if maintenance of LMO4 expression is required for tumor growth as well as identify transcriptional targets of this protein in HER2/Neu-induced tumors. Upon completion of this proposal we will have significantly increased our understanding of the role of activin in tumor-stromal communication, evaluated the potential utility of rapamycin to treat these cancers, and assessed whether LMO4 is an obligate intermediate in tumorigenesis. These studies should reveal additional targets for development of rationally designed therapies for HER2/Neu-induced breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090398-09
Application #
7758369
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Sathyamoorthy, Neeraja
Project Start
2001-03-05
Project End
2012-01-31
Budget Start
2010-03-30
Budget End
2011-01-31
Support Year
9
Fiscal Year
2010
Total Cost
$211,288
Indirect Cost
Name
Case Western Reserve University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106
Seachrist, Darcie D; Bonk, Kristen W; Ho, Shuk-Mei et al. (2016) A review of the carcinogenic potential of bisphenol A. Reprod Toxicol 59:167-82
Yori, Jennifer L; Lozada, Kristen L; Seachrist, Darcie D et al. (2014) Combined SFK/mTOR inhibition prevents rapamycin-induced feedback activation of AKT and elicits efficient tumor regression. Cancer Res 74:4762-71
Sizemore, Steven T; Sizemore, Gina M; Booth, Christine N et al. (2014) Hypomethylation of the MMP7 promoter and increased expression of MMP7 distinguishes the basal-like breast cancer subtype from other triple-negative tumors. Breast Cancer Res Treat 146:25-40
Asrani, Kaushal; Keri, Ruth A; Galisteo, Rebeca et al. (2013) The HER2- and heregulin ?1 (HRG)-inducible TNFR superfamily member Fn14 promotes HRG-driven breast cancer cell migration, invasion, and MMP9 expression. Mol Cancer Res 11:393-404
Bernardo, G M; Bebek, G; Ginther, C L et al. (2013) FOXA1 represses the molecular phenotype of basal breast cancer cells. Oncogene 32:554-63
Seachrist, Darcie D; Johnson, Emhonta; Magee, Christianne et al. (2012) Overexpression of follistatin in the mouse epididymis disrupts fluid resorption and sperm transit in testicular excurrent ducts. Biol Reprod 87:41
Yori, Jennifer L; Seachrist, Darcie D; Johnson, Emhonta et al. (2011) Kruppel-like factor 4 inhibits tumorigenic progression and metastasis in a mouse model of breast cancer. Neoplasia 13:601-10
Beach, Jordan R; Hussey, George S; Miller, Tyler E et al. (2011) Myosin II isoform switching mediates invasiveness after TGF-?-induced epithelial-mesenchymal transition. Proc Natl Acad Sci U S A 108:17991-6
Yori, Jennifer L; Johnson, Emhonta; Zhou, Guangjin et al. (2010) Kruppel-like factor 4 inhibits epithelial-to-mesenchymal transition through regulation of E-cadherin gene expression. J Biol Chem 285:16854-63
Johnson, Emhonta; Seachrist, Darcie D; DeLeon-Rodriguez, Carlos M et al. (2010) HER2/ErbB2-induced breast cancer cell migration and invasion require p120 catenin activation of Rac1 and Cdc42. J Biol Chem 285:29491-501

Showing the most recent 10 out of 22 publications