Abstract

Considerable circumstantial evidence suggests that oncogenes play a role in the development and/or progression of human malignancies. Very little work has been done with human gynecologic neoplasms to test this concept. Our preliminary results show that the HER-2/neu proto-oncogene is amplified and overexpressed in human ovarian cancer and in endometrial cancer. Amplification and expression of the HER-2/neu oncogene will be characterized with Southern hybridization, Northern hybridization, Western immunoblot analysis and immunohistochemistry to determine if amplification is associated with overexpression. Gene amplification will be compared with messenger RNA levels, oncoprotein levels and tissue/cellular distribution of oncoprotein. A computerized image analysis method for quantification of HER-2/neu oncoprotein in individual cells will be developed and used in this investigation. The DNA content of the cancers, considered to be a prognosidc factor in ovarian cancer, will also be determined. Clinical parameters, especially overall patient survival, will be obtained and compared with oncogene amplification and expression as well as DNA ploidy content to determine if there is any correlation between oncoprotein expression, DNA ploidy and unfavorable clinical outcome in women with ovarian or endometrial cancer. In our preliminary data 26% of ovarian cancers had amplification of this oncogene and amplification correlated with a shortened overall patient survival. Since HER-2/neu may be of diagnostic and potentially of therapeutic utility its distribution and expression in normal tissues is critically important. This information is currently unavailable and will be determined as part of the investigation. What role, if any, that wild-type (unmutated) HER-2/neu may play in the pathogenesis of ovarian and/or endometrial cancers is unknown. The transmembrane domain of HER-2/neu gene will be isolated with the polymerase chain reaction and sequenced to determine if the activating point mutation present in mouse tumors is present in human human overian and endometrial cancers. Wild-type HER-2/neu gene will be injected into mousc embryos to produce transgenic mice to determine if this amplified gene is sufficient for the production of malignant tumors. The long-term objective of the current proposal is to determine if the HER-2/neu proto-oncogene is clinically important in human gynecologic neoplasms and to understand the mechanisms by which this cellular oncogene regulates the metabolism of normal and malignant cells of the female reproductive tract

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA050589-02
Application #
3195157
Study Section
Pathology B Study Section (PTHB)
Project Start
1991-02-01
Project End
1994-01-31
Budget Start
1992-02-01
Budget End
1993-01-31
Support Year
2
Fiscal Year
1992
Total Cost
Indirect Cost

  Institution

Name
University of Southern California
Department
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089

  Publications

Saffari, B; Bernstein, L; Hong, D C et al. (2005) Association of p53 mutations and a codon 72 single nucleotide polymorphism with lower overall survival and responsiveness to adjuvant radiotherapy in endometrioid endometrial carcinomas. Int J Gynecol Cancer 15:952-63
Lukas, J; Gao, D Q; Keshmeshian, M et al. (2001) Alternative and aberrant messenger RNA splicing of the mdm2 oncogene in invasive breast cancer. Cancer Res 61:3212-9
Reles, A; Wen, W H; Schmider, A et al. (2001) Correlation of p53 mutations with resistance to platinum-based chemotherapy and shortened survival in ovarian cancer. Clin Cancer Res 7:2984-97
Wen, W H; Bernstein, L; Lescallett, J et al. (2000) Comparison of TP53 mutations identified by oligonucleotide microarray and conventional DNA sequence analysis. Cancer Res 60:2716-22
Wen, W H; Reles, A; Runnebaum, I B et al. (1999) p53 mutations and expression in ovarian cancers: correlation with overall survival. Int J Gynecol Pathol 18:29-41
Lukas, J; Groshen, S; Saffari, B et al. (1997) WAF1/Cip1 gene polymorphism and expression in carcinomas of the breast, ovary, and endometrium. Am J Pathol 150:167-75
Strohmeyer, T; Reese, D; Press, M et al. (1995) Expression of the c-kit proto-oncogene and its ligand stem cell factor (SCF) in normal and malignant human testicular tissue. J Urol 153:511-5
Saffari, B; Jones, L A; el-Naggar, A et al. (1995) Amplification and overexpression of HER-2/neu (c-erbB2) in endometrial cancers: correlation with overall survival. Cancer Res 55:5693-8
Press, M F; Pike, M C; Hung, G et al. (1994) Amplification and overexpression of HER-2/neu in carcinomas of the salivary gland: correlation with poor prognosis. Cancer Res 54:5675-82
Pike, M C; Spicer, D V; Dahmoush, L et al. (1993) Estrogens, progestogens, normal breast cell proliferation, and breast cancer risk. Epidemiol Rev 15:17-35

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