Research Interests
Dr. Dorsey's research is focused primarily on the molecular epidemiology and the molecular genetics of breast cancer. One area of study is the identification of somatic alterations in benign breast biopsies that are predictive of subsequent breast cancer. Through collaboration with the Mayo Clinic, we are evaluating benign breast biopsies and subsequent malignant breast tumor tissues taken from subjects who were part of a large cohort of women who underwent benign breast at the Mayo Clinic during the 1960s and were followed for the development of breast cancer. Women who developed breast cancer became cases, while women who remained free of cancer served as controls. Benign and malignant tissues are being screened for molecular or immunohistochemical changes including p53 mutations or overexpression, HER-2/neu amplification or overexpression, expression of estrogen receptors (ER) alpha and beta, and a point mutation (A908G) in ER alpha.

Studies are also ongoing to assess somatic genetic alterations in breast tumors from the Carolina Breast Cancer Study (CBCS), a population-based, case-control study of invasive breast cancer in North Carolina. We have screened nearly 750 breast tumors from the CBCS for mutations in exons 4-8 of the p53 gene, making this one of the largest studies of p53 in breast cancer to date. The prevalence and spectrum of p53 mutations is being evaluated in relation to potential risk factors for breast cancer, including cigarette smoking, as well as clinical and tumor characteristics. Within the CBCS, we are determining if certain etiologic subsets of in situ and invasive breast cancer are defined by markers of estrogen receptor signaling, including expression of ER-alpha and ER-beta, and the ER-alpha A908G point mutation, or hormone metabolizing enzyme genotypes. The relationship between the presence of somatic ER markers, breast tumor histologic or clinical characteristics, hormonal risk factors and genotypic variation in hormone metabolizing enzymes will be evaluated.

Recent Accomplishments and Honors
Within the Mayo Clinic benign breast disease study, women who had both HER-2/neu amplification and a proliferative histopathologic diagnosis in their benign biopsy were found to have an eight-fold increased risk of developing breast cancer. P53 mutations were also identified in some benign biopsies. Current work is focusing on the detection of ER mutations in benign and malignant breast tissues of this data set.

Within the CBCS, we found a higher prevalence of p53 mutations in the breast tumors of current smokers (36.5%; P=0.02) compared with never smokers (23.6%), while fewer mutations were found in former smokers (16.2%; P=0.09). After adjustment for age, race, menopausal status, clinical stage and tumor size, and family history of breast cancer, current smokers were
significantly more likely to harbor any p53 mutation (OR=2.11; 95% CI=1.17-3.78), p53 transversions (OR=3.37; 95% CI=1.03-11.06), and G:C to T:A transversions (OR=10.53, 95%
CI=1.77-62.55), compared to never smokers. Former smokers were also more likely than never smokers to harbor G:C to T:A transversions (OR=2.43, 95% CI=0.37-15.73). Clinical characteristics, including stage at diagnosis, which were similar among smokers and nonsmokers, did not account for the increase in p53 mutation-positive breast cancer among current smokers. Among former smokers, the prevalence of p53 mutations varied with time since quitting, being highest among recent quitters who stopped smoking within 1 year prior to diagnosis and decreasing thereafter. Our results indicate that cigarette smoking appears to modify the prevalence and spectrum of p53 mutations in breast tumors. Moreover, the difference in mutational spectra observed between smokers and nonsmokers supports the genotoxicity of cigarette smoke in breast tissue. The results of study were highlighted in www.breastlink.org.

Publications
Millikan, R., Hulka, B., Thor, A., Zhang, Y., Edgerton, S., Zhang, X., Pei, H., He, M., Wold, L., Melton, L.J., Ballard, D., Conway, K., Liu, E.T. 1995. p53 mutations in benign breast tissue. J. Clin. Oncol. 13: 2293-2300.

Conway, K., Edmiston, S.N., Hulka, B.S., Garrett, P.A., Liu, E.T. 1996. Internal sequence variations in the Ha-ras VNTR rare and common alleles identified by minisatellite variant
repeat (MVR)-polymerase chain reaction (PCR). Cancer Res. 56: 4773-4777.

Olshan, A.F., Weissler, M.C., Pei, H., Conway, K., Anderson, S., Fried, D.B., Yarborough, W.G. 1997. Alterations of the p16 gene in head and neck cancer: frequency and association with p53, Prad-1 and HPV. Oncogene 14: 811-818.

Olshan, A.F., Weissler, M.C., Pei, H., Conway, K. 1997. P53 mutations in head and neck cancer: new data and evaluation of mutational spectra. Cancer Epidem., Biomark. Prev., 6: 499-504.

Stark, A., Hulka, B.S., Joens, S., Novotny, D., Thor, A.D., Wold, L., Liu, E.T., Conway, K. 2000. HER-2/neu amplification in benign breast disease and the risk of subsequent breast cancer. J. Clin. Oncol. 18: 267-274.

Huang, W.-Y., Newman, B., Millikan, R.C., Conway, K., Hulka, B.S., Schell, M.J., Liu, E.T. 2000. Risk of breast cancer according to the status of Her-2/neu oncogene amplification. Cancer
Epid., Biomark. Prev. 9:65-71.

Conway, K., Edmiston, S., Cui, L., Drouin S, Pang, J., Tse, C.-K., Geradts J, Dressler L, Li, E.T., Millikan R, Newman, B. 2002. The prevalence and spectrum of p53 mutations associated with smoking in breast cancer. Cancer Res. 62: 1987-1995.

Millikan R, Eaton A, Worley K, Biscocho L, Hodgson E, Huang W-Y, Geradts J, Iacocca M, Cowan D, Conway K, Dressler L. 2003. HER2 codon 655 polymorphism and risk of breast cancer in African Americans and whites. Breast Cancer Res Treat. 79: 355-364.

E-mail: kconway@med.unc.edu
Telephone: (919) 966-2180 / 962-3405
Address: 359 Rosenau Hall Chapel Hill, NC

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