Abstract
B71
Introduction: Recently the triple negative (TNT) breast cancers were found to be especially frequent in young African-American women. TNT does not express the breast cancers markers estrogen receptor (ER), progesterone receptor (PR), and epidermal growth factor type 2 (Her-2/neu), which are currently used in patient management decisions. These tumors have an unfavorable course and there is no targeted therapy available. They frequently express EGFR and p53 positivity. The molecular events leading to this particularly aggressive breast carcinoma are not fully understood. Objective: To determine the molecular events leading to the development of triple negative invasive tumor cells, we examined the changes of biomarkers in MCF-10A serial cell lines that represent different stages of breast cancer development in vitro and in vivo in xenografted tumors derived from those cell lines.Methods: MCF-10DCIS or MCF-10CA1 tumor cells were inoculated subcutaneously into nude mice for 4 weeks. The mice were treated with an EGFR inhibitor for 4 weeks and tumors from the untreated and treated mice from these cell lines were evaluated for size, harvested and embedded in paraffin. Paraffin tissue sections from representative tumors were examined by histopathological and Immunohistochemical (IHC) analysis. Results: The xenografted tumors derived from MCF-10DCIS cells contain both DCIS-like architecture and frank invasive tumor areas while the MCF-10CA1 tumors consist entirely of invasive tumor cells. The xenograft tumors derived from MCF-10DCIS cells contain mixed DCIS and invasive tumor areas while the MCF-10CA1 tumors entirely consist of invasive tumor cells. Both MCF-10DCIS and CA1 tumors are negative for ER and PR. In addition, MCF-10DCIS lesions express EGFR (50%), CD44 (85%), Ki-67 (90%), up to 8% p53 positivity and HER-2 (60%). The tumors derived from MCF-10CA1 show a TNT phenotype, and are positive for p53 (20%), EGFR (100%), CD44 (100%) and up to 75% Ki-67 positivity. After treatment the MCF-10DCIS generated tumors with a EGFR inhibitor, Tarceva, for four weeks, about 50 % of tumor growth inhibition was detected in the xenografted tumors. Histological examination showed a 15% decrease in EGFR expression and 5% in CD44, 2% increased p53 expression while the proliferation marker Ki-67 remained basically unchanged. In MCF-10CA1 tumors, Tarceva treatment resulted in 50% reduction in tumor mass, 50% decrease in p53 and 10% decrease in expression of the proliferation marker Ki-67 in the MCF-10CA1 generated tumors. Conclusions: We have developed an animal tumor model that allows for study of the breast tumor biology and development, especially for the determination of the role of triple negative (ER, PR, Her-2) tumor cells in breast cancer progression and resistance to therapy. In addition EGFR and p53 expression in these tumors, similar with TNT breast cancers, makes them well suited for further TNT molecular studies.
First AACR International Conference on the Science of Cancer Health Disparities-- Nov 27-30, 2007; Atlanta, GA