Abstract 5467: Green tea catechin intervention of human breast cell carcinogenesis chronically induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Abstract

Abstract The purpose of our study was to investigate the mechanism by which dietary carcinogen 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces breast cell carcinogenesis. More than 85% of breast cancers are sporadic and attributable to long-term exposure to environmental factors, such as carcinogens in the diet, through a multi-step disease process progressing from non-cancerous to premalignant and malignant stages. The dietary carcinogen PhIP is one of the most abundant heterocyclic amines found in high-temperature cooked meats and is recognized as a mammary carcinogen. Here, we demonstrated, for the first time, that cumulative exposures to PhIP at physiologically-achievable, pico- to nano-molar concentrations effectively induced progressive carcinogenesis of human breast epithelial MCF10A cells from a non-cancerous stage to premalignant and malignant stages in a dose- and exposure-dependent manner. Progressive carcinogenesis was measured by increasingly-acquired, cancer-associated properties of reduced dependence on growth factors, anchorage-independent growth, acinar-conformational disruption, proliferation, migration, invasion, tumorigenicity with metastasis, and increased stem-like cell populations. These biological changes were accompanied by biochemical and molecular changes, including upregulated H-Ras gene expression, ERK pathway activation, Nox-1 expression and reactive oxygen species (ROS) elevation. The Ras-ERK-Nox-ROS pathway played an important role in not only initiation but also maintenance of cellular carcinogenesis induced by PhIP. Using biological, biochemical, and molecular changes as targeted endpoints, we identified that the green tea catechin components, at non-cytotoxic doses, were capable of suppressing PhIP-induced cellular carcinogenesis and tumorigenicity. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5467. doi:1538-7445.AM2012-5467