The Prognostic Impact of Intratumoral Aryl Hydrocarbon Receptor in Primary Breast Cancer Depends on the Type of Endocrine Therapy: A Population-Based Cohort Study

Abstract

The aryl hydrocarbon receptor (AhR) is a master regulator of multiple pathways involved in breast cancer, and influences the estrogen receptor alpha (ER) and aromatase/CYP19A1. The purpose of this study was to elucidate the interplay between intratumoral levels of AhR and aromatase, patient characteristics (including AhR and CYP19A1 genotypes), clinicopathological features, and prognosis in breast cancer patients receiving adjuvant treatments. A prospective cohort of 1116 patients with primary breast cancer in Sweden, included 2002–2012, was followed until June 30th 2019 (median 8.7 years). Tumor‐specific AhR (n=920) and aromatase levels (n=816) were evaluated on tissue microarrays using immunohistochemistry. Associations between cytoplasmatic (AhRcyt) and nuclear (AhRnuc) AhR levels, intratumoral aromatase, clinicopathological features, and prognosis in different treatment groups were analyzed. Low AhRcyt levels (n=183) and positive intratumoral aromatase (n=69) were associated with estrogen receptor (ER)– status and more aggressive tumors. Genotypes were not associated with their respective protein levels. The functional AhRArg554Lys GG genotype was associated with recurrence-free survival in switch-therapy (sequential tamoxifen/aromatase inhibitors (AI) or AI/tamoxifen) treated patients (HRadj 0.42; 95% CI 0.22–0.83). High AhRcyt levels were associated with longer recurrence-free survival during the first 10 years of follow-up among tamoxifen-only treated patients (HRadj 0.40; 95% CI 0.23–0.71) compared to low AhRcyt levels, whereas an almost inverse association was seen in patients with switch-therapy (Pinteraction=0.023). Intratumoral aromatase had little prognostic impact. These findings warrant confirmation in an independent cohort, preferably in a randomized clinical trial comparing different endocrine regimens. They might also guide the selection of breast cancer patients for clinical trials with selective AhR modulators.

Association between estrogen receptor alpha and aryl hydrocarbon receptor gene polymorphisms in the prognosis of breast cancer in Egypt

“…10 Contrasting our proposition, Tryggvadottir et al, 2021, suggested that AhR was strongly associated with patients' ER-negative. 11 However, similar to Tryggvadottir et al, 2021 study findings, we reported that there was a statistically significant difference between AhR allelic variants and progesterone status. 11 However, this was not in agreement with findings of a study by Vacher et al, 2018.…”

“…11 However, similar to Tryggvadottir et al, 2021 study findings, we reported that there was a statistically significant difference between AhR allelic variants and progesterone status. 11 However, this was not in agreement with findings of a study by Vacher et al, 2018. 12 Benoit et al, 2022 suggested that there was over-expression of AhR in HER2 negative cells but not over-expression in HER2 receptor.…”

“…Our study revealed that breast patients who carried AhR (GG), Xbal (AA), and PvuII (TT) genotypes had a better prognosis, this agreed with findings of previous studies. 4,11,16 In conclusion, the polymorphic variation of positive genotypes of PvuII, XbaI, and AhR polymorphisms is highly associated with better prognosis in breast cancer patients. Negative genotypes of PvuII, XbaI, and AhR polymorphisms are strong and significantly prevalent in poor-prognostic breast cancer patients…”

The Role of the Aryl Hydrocarbon Receptor (AhR) and Its Ligands in Breast Cancer

“…There were some differences in the nuclear and extranuclear distribution of AhR protein in non-pathological breast ductal epithelial cells and invasive ductal carcinoma and AhR overexpression was associated with better prognosis of ER-negative and ER-positive invasive ductal carcinoma patients [ 58 ]. In another study on 436 breast cancer cases, it was concluded “that AhR expression is not a prognostic factor in breast cancer” [ 59 ]. There were correlations between AhR, and levels of several genes associated with inflammation and high levels of AhR repressor (AhRR) mRNA which predicted enhanced patient survival.…”

“…Another report indicated that the predictive value of the AhR was dependent on the lymph node status of the patient and concluded “that AhR is a marker of poor prognosis for patients with LN-negative luminal-like BCs” [ 61 ]. The results suggest that the prognostic value of AhR levels (mRNA and protein), intracellular location and AhR polymorphisms with respect to patient survival/disease recurrence is complex and dependent on many other factors, including prior patient treatment protocols [ 58 , 59 , 60 , 61 ].…”