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Signatures of High Risk Premalignant Breast Lesions and Therapeutic Targets for Prevention of Breast Cancer

The Challenge

Accurate prediction of risk and personalized approaches to prevention of breast cancer or its recurrence are needed to reduce both cost of treatment and morbidity.

The Innovation/Technology

We have developed gene expression signatures that distinguish premalignant breast lesions in women providing biomarkers to improve diagnosis and identify therapeutic targets. Primary explant cultures of human breast tissues retain estrogen and progesterone receptors and are used to determine the spectrum and variation in responses to estrogenic compounds and drugs. Conditionally immortalized primary breast cell cultures provide tools for screening responses to therapies and genetic engineering of cells. Our work in primary human tissues is paralleled by transplantable models of premalignancy and tumors in immunocompetent mice. These are suitable for preclinical studies of cancer immunotherapies.

The Impact

Accurate diagnostic tools for premalignancy would allow early interventions preventing as many as 10,000 cases of breast cancer annually in the US. The tests would also reduce the “overdiagnosis” of breast cancer that has led to the unnecessary treatment of early lesions that would not have progressed to cancer as well as more targeted therapies for the subset of women who are at greatest risk.

The Solution

Detection of early lesions provides the greatest opportunity to successfully treat cancer. However, diagnostic tests to accurately identify the lesions that will progress from those that remain latent and selecting effective therapies are needed. The challenge is exemplified by our demonstration of p53 mutations predisposing to mammary tumors in one mouse strain while another strain is nearly completely resistant. This underscores the fact that even a powerful genetic lesion such as p53 mutations can have very different consequences in different patients.

We have sought to utilize clinical specimens to define patterns of gene expression that distinguish early breast lesions (atypical hyperplasias) that subsequently progress to invasive cancer from those that remain indolent. To accomplish this, we have optimized methods for microdissection of lesions from formalin-fixed clinical specimens and amplification of RNA to yield robust gene expression profiles. This project builds on our prior experience in developing gene expression signatures defining the effects of hormonal exposures in breast tissues from mice and women.

We have also collected primary breast epithelial cells from patients to create a panel representing the genetic diversity of the population. The cells can be modified using gene editing to test the effects of oncogenes in different patients. We also utilize explant cultures of breast tissues that maintain the architecture and responses to estrogen and progesterone. These results emphasize the wide range of responsiveness among women and the different effects of ligands binding to the subtypes of estrogen receptors (alpha and beta). Studies in mice have shown that ligands selectively binding to estrogen receptor beta enhance genome surveillance via the p53 pathway. Hormonal regulation of p53 provides opportunities for chemoprevention.

Photos: Parallel studies in mice and human tissues are used to identify conserved pathways that can confer risk and can be harnessed to promoter resistance to breast cancer.

Publications
Jerry, D.J., Kittrell, F.S., Kuperwasser, C., Laucirica, R., Dickinson,E.S., Bonilla, P.J., Butel, J.S., and Medina, D. 2000. A mammary-specific model demonstrates the role of the p53 tumor suppressor gene in tumor development. Oncogene 19(8):1052-1058. PMID: 10713689
Yan, H., Blackburn, A.C., McLary, S.C., Tao, L., Roberts, A.L., Xavier, E.A., Dickinson, E.S., Seo, J.H., Arenas, R.B., Otis, C.N., Cao, Q.J., Lawlor, R.G., Osborne, B.A., Kittrell, F.S., Medina, D. and Jerry, D.J. 2010. Pathways contributing to development of spontaneous mammary tumors in BALB/c-Trp53+/- mice. Am. J. Pathol. 176(3):1421-32. PMID: 20110418; PMCID: PMC2832161
Tao, L., Roberts, A.L., Dunphy, K.A., Bigelow, C., Yan, H., and Jerry, D.J. 2011. Repression of mammary stem/progenitor cells by p53 is mediated by notch and separable from apoptotic activity. Stem Cells 29(1):119-27. PMID: 21280161; PMCID: PMC3404152
Sun X, Casbas-Hernandez P, Bigelow C, Makowski L, Jerry DJ, Smith Schneider S, Troester MA. 2012. Normal breast tissue of obese women is enriched for macrophage markers and macrophage-associated gene expression. Breast Cancer Res Treat. 131(3):1003-12. PMID: 22002519; PMCID: PMC3640411
Pirone, J.R., D’Arcy,M., Stewart, D.A., Hines, W.C., Johnson, M.A., Gould, M.N., Yaswen, P., Jerry, D.J., Schneider, S.S., Troester, M.A. 2012. Age-associated gene expression in normal breast tissue mirrors qualitative age-at-incidence patterns for breast cancer. Cancer Epidemiol. Biomarkers Prev. 21(10):1735-44. PMID: 22859400; PMCID: PMC3684707
Dunphy, K.A., Seo, J.-H., Kim, D.J., Roberts, A.L., Tao, L., DiRenzo, J., Balboni, A.L., Crisi, G.M., Hagen, M.J., Chandrasekaran, T., Gauger, K.J., Schneider, S.S. and Jerry, D.J. 2013. Oncogenic transformation of mammary epithelial cells by Transforming Growth Factor beta independent of mammary stem cell regulation. Cancer Cell Int. Cancer Cell Int. 2013 Jul 25;13(1):74. PMID: 23883065; PMCID: PMC3733955