Basic research remains critical for our interpretation and improvement of ongoing chemo-endocrine breast cancer protocols. Our prototype model of tamoxifen-5fluorouracil (TAM-FUra) modulation remains the only in vitro example of chemo-endocrine synergy reported to date, and this project will continue to explore oncogenes (c-myc, c-fos, c-erbB-2) and estrogen receptors (ER) as targets for RNA-directed chemo-endocrine therapy. Human breast cancer cell lines will be used to i) complete studies comparing antiestrogen effects on c-myc and c-fos expression, ii) establish the therapeutic impact of inhibiting endogenous c-erbB-2 expression by transfecting antisense-erbB-2 genes, and iii) identify and characterize the small RNA species (RNAt) isolated from in vitro bound complexes of ER with its cognate DNA response element, ERE. Northern blot hybridization, nuclear run-on and in vitro transcript splicing assays will differentiate effects on c-myc and c-fos mRNA metabolism resulting from anti-estrogen therapy; and modulation of protein kinase C activity will help to determine if this signal transduction pathway is involved in these antiestrogen effects. Transfection of a constitutively promoted 5'-antisense-erbB-2 vector appears to inhibit growth of only those breast cancer cells showing deregulated endogenous c-erbB-2 overexpression; and further analysis of sense vs. antisense transfected subclones is necessary to document changes induced in c-erbB-2 transcript rates, mRNA and protein (pl85erbB-2) levels. Antisense-erbB-2 genes driven by inducible promoters (MMTV, hsp-70) will also be constructed to deliver the antisense response in combination with drug or endocrine therapy. Lastly, preliminary studies support a new model of ER gene activation involving a 4S RNA species (RNAt) that is necessary for and contained within in vitro ER-ERE complexes. Gel-shift will be used to purify RNAt, and to characterize its binding with ER and ERE. A therapeutic role for RNAt will be looked for by comparing drug and endocrine effects on ER-ERE complexes formed either in vitro or in vivo. These studies will hopefully provide new rationale and direction for improved chemo-endocrine therapies of breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA036773-09
Application #
3174339
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Project Start
1983-08-15
Project End
1995-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
9
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Scott, Gary K; Goga, Andrei; Bhaumik, Dipa et al. (2007) Coordinate suppression of ERBB2 and ERBB3 by enforced expression of micro-RNA miR-125a or miR-125b. J Biol Chem 282:1479-86
Zhou, Yamei; Yau, Christina; Gray, Joe W et al. (2007) Enhanced NF kappa B and AP-1 transcriptional activity associated with antiestrogen resistant breast cancer. BMC Cancer 7:59
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Scott, Gary K; Mattie, Michael D; Berger, Crystal E et al. (2006) Rapid alteration of microRNA levels by histone deacetylase inhibition. Cancer Res 66:1277-81
Neve, Richard M; Parmar, Hema; Amend, Cliff et al. (2006) Identification of an epithelial-specific enhancer regulating ESX expression. Gene 367:118-25

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