Abstract
Breast cancer is the most commonly diagnosed malignancy in females, the etiology being multifactorial and includes the role of lifestyle exposure to DNA-damaging chemicals such as dietary carcinogens benzo (a) pyrene (BaP) and 2-amino-1-methyl-6-phenylimidazo [4, 5-b] pyridine (PhIP). Both compounds require cytochrome P450 (CYP)-mediated metabolic activation to DNA-damaging species, and both induce transcriptional responses through the nuclear receptors Aryl hydrocarbon receptor (AhR) and estrogen receptor α (ERα). BaP and PhIP are mammary carcinogens in rodents. Clinically, circulating IL-6 expression is linked with poor prognosis of cancer and 35% of the deaths in breast cancer are linked with inflammation. The objective of this work was to investigate the molecular toxicology and local activation of BaP and PhIP in the presence of IL-6. Our laboratory has previously reported that miR27b can regulate CYP1B1 expression in colorectal cells, here we have investigated if this mechanism is working in mammary cell models, MCF-7 and MDA-MB-231 cells. Treatment (24 h) of cells with BaP (10 nM-10 µM) and PhIP (100 nM-100 µM) significantly induced genetic damage (micronuclei formation) in a dose-dependent manner in both cell lines. This effect was potentiated in the presence of human IL-6 at concentrations reported to be expressed in clinical breast cancer. On its own, IL-6 treatment failed to induce micronuclei frequency above the control levels in these cells. Compared to BaP or PhIP treatment alone, IL-6 plus BaP or PhIP selectively induced CYP1B1 significantly in both cell lines. Additionally, miR27b expression was downregulated by IL-6 treatments and transfection with miR27b inhibitor confirmed that miR27b is a regulator of CYP1B1 in both cell lines. These data show that BaP- and PhIP-induced DNA damage in mammary cells is potentiated by the inflammatory cytokine IL-6 and that inflammation-induced CYP expression, specifically CYP1B1 via miR27b, is responsible for this effect.
Highlights
Epidemiological studies suggest that chronic inflammation increases the susceptibility of individuals to various types of cancer and is linked with 15–20% of all deaths from cancer worldwide (Bray et al 2004; Mantovani et al 2008)
The expression of CYP1A1, CYP1A2 and CYP1B1 was inducible by BaP treatment in a dose-dependent manner; the magnitude of the induction was greatest for CYP1A1 and CYP1B1 in both cell lines (Table 1)
In breast cancer, elevated circulating levels of pro-inflammatory cytokine IL6 have been linked with poor prognosis (Zhang and Adachi 1999; Fouad et al 2014), and consumption of a pro-inflammatory diet is associated with an increased incidence of breast cancer (Shivappa et al 2015)
Summary
Epidemiological studies suggest that chronic inflammation increases the susceptibility of individuals to various types of cancer and is linked with 15–20% of all deaths from cancer worldwide (Bray et al 2004; Mantovani et al 2008). BaP and PhIP are pro-carcinogens and are activated by CYP1 family A1, A2 and B1 enzymes into their genotoxic derivatives that bind covalently with DNA, disrupting the double helical structure leading to DNA damage (Strom and Michalopoulos 1982; Heussen et al 1990; Boobis et al 1994; Zhao et al 1994; Kranendonk et al 1998; Lynch et al 1998; Gooderham et al 2002, 2007). Activation of these CYP enzymes can increase the mutagenicity of various pro-carcinogens
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