Abstract
Increasing epidemiological and animal experimental data provide substantial support for the role of aryl hydrocarbon receptor (AhR) in mammary tumorigenesis. The effects of AhR have been clearly demonstrated in rodent models of breast carcinogenesis and in several established human breast cancer cell lines following exposure to AhR ligands or AhR overexpression. However, relatively little is known about the role of AhR in human breast cancers. AhR has always been considered to be a regulator of toxic and carcinogenic responses to environmental contaminants such as TCDD (dioxin) and benzo[a]pyrene (BaP). The aim of this study was to identify the type of breast tumors (ERα-positive or ERα-negative) that express AHR and how AhR affects human tumorigenesis. The levels of AHR, AHR nuclear translocator (ARNT) and AHR repressor (AHRR) mRNA expression were analyzed in a cohort of 439 breast tumors, demonstrating a weak association between high AHR expression and age greater than fifty years and ERα-negative status, and HR-/ERBB2 breast cancer subtypes. AHRR mRNA expression was associated with metastasis-free survival, while AHR mRNA expression was not. Immunohistochemistry revealed the presence of AhR protein in both tumor cells (nucleus and/or cytoplasm) and the tumor microenvironment (including endothelial cells and lymphocytes). High AHR expression was correlated with high expression of several genes involved in signaling pathways related to inflammation (IL1B, IL6, TNF, IL8 and CXCR4), metabolism (IDO1 and TDO2 from the kynurenine pathway), invasion (MMP1, MMP2 and PLAU), and IGF signaling (IGF2R, IGF1R and TGFB1). Two well-known ligands for AHR (TCDD and BaP) induced mRNA expression of IL1B and IL6 in an ERα-negative breast tumor cell line. The breast cancer ER status likely influences AhR activity involved in these signaling pathways. The mechanisms involved in AhR activation and target gene expression in breast cancers are also discussed.
Highlights
Breast cancer is the most common cancer in women in Western countries
AHR mRNA expression level was weakly associated with estrogen receptor alpha (ERα) and hormone receptor (HR) negative status (p = 0.039 and p = 0.018, respectively) and HR-/human epidermal growth factor receptor 2 (ERBB2)- breast cancer subtypes (p = 0.047) (Table 2)
In order to confirm the implication of AHR in the regulation of inflammation genes, we examined the effect of two AHR ligands: TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) and BaP, on mRNA expression of several inflammation genes: IL1B, IL6, TNF, IL8 and CXCR4, in MDA-MB-436 ERα-negative breast cancer cells
Summary
All of the established risk factors combined can only explain less than half of all cases of breast cancer [1,2]. Epidemiological studies conducted after the “Seveso accident”, one of the best known industrial accidents, and studies on chemical workers exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin) [6] have revealed increased risks of developing breast cancer following exposure to TCDD, a potent ligand of the aryl hydrocarbon nuclear receptor (AhR). Breast cancer incidence increased even more than 15 and 30 years after the Seveso accident [7,8,9]. Growing evidence from animal studies, including those performed on TCDD-exposed rodents during gestation, and on a number of established human breast cancer cell lines, provides substantial support for the role of AhR in mammary tumorigenesis. Relatively little is known about the role of AhR in human primary breast tumors
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