PO-001 Environmental toxins can transform mammary cells and induce chemo-resistance in breast cancer via multiple mechanisms

• Published in: ESMO open Vol. 3; p. A21
• Main Authors: Abdel-Rahman, W.M., Aravind, S.R., Nair, V.A., Bajbouj, K., Valo, S., Peltomäki, P.
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 30.06.2018
• ISSN: 2059-7029; 2059-7029
• DOI: 10.1136/esmoopen-2018-EACR25.46

There is an ample epidemiological and in vivo evidence to support the role of environmental contaminants such as bisphenol A (BPA) in breast cancer development but the role of other contaminants and the molecular mechanisms of action of many toxins, including BPA, are still not fully understood. We sought to elucidate the various effects of six common contaminants: BPA, methoxychlor (MXC), hexabromocyclododecane (HBCD), 4-nonylphenol (NP), 4-tert-octylphenol (OP), and 2-Amino-1-methyl-6-phenylimidazo [4,5-b] pyridine (PhIP) using mammary epithelial cell (hTERT-HME1) and a breast cancer cell line of low malignant potential (MCF7). We analysed various effects by cell viability, Annexin 5 and caspases activity detection by ELISA, Western blot for DNA damage markers, Flowcytometry, methylation analysis of 24 tumour suppressor genes, collagen invasion and colony formation in soft agar. We found that low dose (0.001 uM) of these agents prolonged cell viability and induced resistant to chemotherapy due to abrogation of apoptosis through both intrinsic and extrinsic pathways. Toxic agents induced DNA damage (evidenced by upregulation of pH2A.X, pCHK1, pCHK2, p-P53) and various cell cycle alterations of which increased G2-M fraction was common. Some of these agents induced epigenetic (methylation) changes of tumour suppressor genes TIMP3, CHFR, ESR1, IGSF4, CDH13 and GSTP1. Obviously, the accumulation of these molecular alterations is an essential base for cancer development. Consistent with this, we observed that two-month exposure to low dose of these agents increased both cellular invasiveness through collagen and cellular abilities to form colonies in soft agar. Some agents induced proteins kinase phosphorylation of EGFR, HSP60, HSP27, AMPKα1, FAK, c-Jun, p53, GSK-3α/β, P70S6, all of which are involved in potential carcinogenic pathways. Overall, these data supply an evidence to implicate some common environmental contaminants in breast carcinogenesis which is a good foundation to understanding and prevention of environmental carcinogenesis.