Cellular growth factors and growth factor receptors play important regulatory roles in tumor cells and can effect expression of malignant phenotype and biological aggressiveness. Alterations in selected hormone receptors and growth factors of potential clinical importance in breast cancer are the focus of this competitive renewal application. Estrogen receptor (ER) and progesterone receptor (PR) are of prognostic significance in breast cancer and in predicting clinical response to endocrine therapy for women with recurrent disease. Recently, variant ER and PR have been described in breast cancer cell lines and breast cancers suggesting an explanation for ER-positive, PR-positive breast cancers which fail endocrine management. single-strand conformational polymorphism and direct DNA sequencing will be used to identify and characterize alterations in expression of ER and PR genes. Complementary DNA coding for ER and PR will be obtained from normal endometrial mRNA and compared with published sequences obtained from breast carcinoma cell lines to determine if any ER or PR alterations were present in the described cell lines. HER-2/neu proto-oncogene, which codes for a membrane receptor, has been reported to be of prognostic significance in women with node-positive breast cancer. The predictive value of this oncogene in node-negative breast cancer is quite controversial. Since most studies of HER-2/neu expression have been immunohistochemical studies of archival tissue, we will evaluate the antibodies used in these reports to determine their relative sensitivity. Breast cancers from a large cohort of women with node-negative breast cancer will also be assessed for HER-2/neu amplification-overexpression and these results will be compared with disease-free interval and overall survival. With the advent of mammography more women are being diagnosed with breast cancer at an earlier stage and methods of analyzing gene amplification and overexpression in very small samples is needed. Quantitative polymerase chain reaction and fluorescence in situ hybridization will be assessed as methods for evaluating HER-2/neu gene amplification. Immunohistochemistry can be used for evaluating expression in small invasive cancers but in a subjective fashion. Work with computerized image analysis will continue and a technique for reporting immunohistochemical staining as a quantitative result will be developed. It is anticipated that the newly identified human ligand for HER-2/neu, heregulin, will have important biological effects. Heregulin expression will be characterized in normal tissues and breast cancers. The effect of heregulin on DNA content of tumor cells will be evaluated in HER-2/neu engineered cell lines. The long term objective of these investigations is to understand the mechanisms by which hormones and their respective receptors regulate the metabolism of normal and malignant breast cells. This combination of basic investigations is expected to provide new information which will be useful in the clinical management of women with breast cancer.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA048780-08
Application #
2093069
Study Section
Pathology B Study Section (PTHB)
Project Start
1988-04-01
Project End
1998-01-31
Budget Start
1995-02-01
Budget End
1996-01-31
Support Year
8
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Southern California
Department
Pathology
Type
Schools of Medicine
DUNS #
041544081
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Stern, Howard M; Gardner, Humphrey; Burzykowski, Tomasz et al. (2015) PTEN Loss Is Associated with Worse Outcome in HER2-Amplified Breast Cancer Patients but Is Not Associated with Trastuzumab Resistance. Clin Cancer Res 21:2065-74
Slamon, Dennis; Eiermann, Wolfgang; Robert, Nicholas et al. (2011) Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med 365:1273-83
Press, Michael F; Sauter, Guido; Buyse, Marc et al. (2011) Alteration of topoisomerase II-alpha gene in human breast cancer: association with responsiveness to anthracycline-based chemotherapy. J Clin Oncol 29:859-67
Ma, Huiyan; Wang, Yaping; Sullivan-Halley, Jane et al. (2010) Use of four biomarkers to evaluate the risk of breast cancer subtypes in the women's contraceptive and reproductive experiences study. Cancer Res 70:575-87
Ma, Huiyan; Wang, Yaping; Sullivan-Halley, Jane et al. (2009) Breast cancer receptor status: do results from a centralized pathology laboratory agree with SEER registry reports? Cancer Epidemiol Biomarkers Prev 18:2214-20
Press, Michael F; Sauter, Guido; Bernstein, Leslie et al. (2005) Diagnostic evaluation of HER-2 as a molecular target: an assessment of accuracy and reproducibility of laboratory testing in large, prospective, randomized clinical trials. Clin Cancer Res 11:6598-607
Agus, David B; Gordon, Michael S; Taylor, Charles et al. (2005) Phase I clinical study of pertuzumab, a novel HER dimerization inhibitor, in patients with advanced cancer. J Clin Oncol 23:2534-43
Mass, Robert D; Press, Michael F; Anderson, Steven et al. (2005) Evaluation of clinical outcomes according to HER2 detection by fluorescence in situ hybridization in women with metastatic breast cancer treated with trastuzumab. Clin Breast Cancer 6:240-6
Dybdal, Noel; Leiberman, Grazyna; Anderson, Steven et al. (2005) Determination of HER2 gene amplification by fluorescence in situ hybridization and concordance with the clinical trials immunohistochemical assay in women with metastatic breast cancer evaluated for treatment with trastuzumab. Breast Cancer Res Treat 93:3-11
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

Showing the most recent 10 out of 43 publications