Abstract
Increasing evidence implicates the aryl hydrocarbon receptor (AhR) as a possible regulator of mammary carcinogenesis. This study aims to clarify its prognostic impact in breast cancer (BC). Meta-analyses performed at the mRNA level demonstrated that the predictive value of AhR expression in BC depends on the lymph node (LN) status. AhR expression and sub-cellular location were then analyzed by immunohistochemistry in 302 primary BC samples. AhR was expressed in almost 90% of cases with a predominant nuclear location. Nuclear and cytoplasmic AhR levels were significantly correlated and associated with the expression of RIP140 (receptor-interacting protein of 140 kDa), an AhR transcriptional coregulator and target gene. Interestingly, total and nuclear AhR levels were only significantly correlated with short overall survival in node-negative patients. In this sub-group, total and nuclear AhR expression had an even stronger prognostic impact in patients with low RIP140-expressing tumors. Very interestingly, the total AhR prognostic value was also significant in luminal-like BCs and was an independent prognostic marker for LN-negative patients. Altogether, this study suggests that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs, which warrants further evaluation.
Highlights
Breast cancer (BC) is a global public health issue and the most commonly diagnosed neoplasm in the world [1]
These results suggest that aryl hydrocarbon receptor (AhR) expression may influence patient survival according to the lymph node (LN) status
This study demonstrates that AhR is expressed in the majority of breast cancer (BC) tissues and may play differential roles in breast tumorigenesis according to both its subcellular location and the degree of metastatic progression
Summary
Breast cancer (BC) is a global public health issue and the most commonly diagnosed neoplasm in the world [1]. The expression of estrogen receptor α (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) is widely accepted as prognostic and predictive markers and considered suitable to guide treatment decisions (endocrine- or anti-HER2-targeted therapies) [2]. AhR is a transcription factor which is activated by ligands (such as dioxin [4]) and translocates from the cytoplasm to the nucleus. It dimerizes with ARNT (AhR nuclear transporter), leading to the regulation of target genes implicated in several diseases, including cancer [5]. The transcriptional coregulator RIP140 (Receptor Interacting Protein of 140 kDa) interacts with AhR and acts as a coactivator of its ligand-induced activity [6]. RIP140 appears to be an AhR target gene in BC cells, since its expression is induced by dioxin [7]
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