Abstract 3454: Molecular markers for breast carcinogenesis models induced by environmental substances and estrogen

Abstract

Abstract Breast cancer is the most common cancer in women throughout the world. Exogenous and endogenous agents such as environmental carcinogens and female hormones seem to be involved in the etiology of breast cancer. It is a multistage process involving a series of genetic alterations, identification of potential genes responsible for breast carcinogenesis is critical for timely diagnosis and prevention of breast cancer. To gain insights into the mechanisms for breast cancer initiation and development processes by exogenous environmental agents, we have developed many experimental breast cancer model systems: In vitro model with the immortalized human breast epithelial cell line, MCF-10F exposed to (I) low doses of high LET (linear energy transfer) alpha particles (150 keV/μm) (Carcinogenesis 21: 769, 2000) and b), (II) organophosphorous pesticides, either with Parathion (P) or Malathion (M) and (III) combination of either P or M in the presence of estrogen (E). Results showed that MCF-10F cells treated either with double dose of 60 cGy alpha particles in the presence of E or pesticides induced malignant transformation of MCF-10F. The malignant transformation was determined by multiple biological assays: increased cell proliferation, anchorage independency, invasive capabilities and tumor formation in nude mice, microsatellite instability and loss of heterozygosity in chromosomes 17, 11, 6, 8. Gene expression analysis using cancer pathway specific and affymetrix arrays detected alterations in the expression levels of p53, ErbB2, BRCA1, c-Ha-ras, Rho-A, PTEN, RB, c-Ha-ras, transforming protein Rho-A, F, GDP, TGF alpha, beta receptor, integrin B6, Notch3 and cathepsin. In addition to the in vitro human model, in vivo rat mammary gland model was also generated: (I) control (II) either P or M (III) E and (IV) P or M and E. Animals were treated for 5 days. These combined treatments induced significant progressive morphological and molecular changes. Alterations in the expression levels of RNA and protein were observed for c-fos, c-myc, mutant p53, ErbB2, BRCA1, c-Ha-ras, Rho-A, CYP1A1 gene and protein expression in the rat mammary gland after 240 days of treatment in comparison to control. Such stimulation led to mammary tumor formation. Collectively, our study shows the molecular signature of oncogenic deregulation in breast cancer progression induced by the combination of environmental substances and estrogen. Thus, aberrant expression of multiple genes involved in key signaling pathways renders these models as important tools for monitoring carcinogenic progression and chemo-intervention. Grant FONDECYT # 1080482 (GMC). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3454.