AhR ligand aminoflavone suppresses α6‐integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells

Abstract

More than 40% of patients with luminal breast cancer treated with endocrine therapy agent tamoxifen demonstrate resistance. Emerging evidence suggests tumor initiating cells (TICs) and aberrant activation of Src and Akt signaling drive tamoxifen resistance and relapse. We previously demonstrated that aryl hydrocarbon receptor ligand aminoflavone (AF) inhibits the expression of TIC gene α6-integrin and disrupts mammospheres derived from tamoxifen-sensitive breast cancer cells. In the current study, we hypothesize that tamoxifen-resistant (TamR) cells exhibit higher levels of α6-integrin than tamoxifen-sensitive cells and that AF inhibits the growth of TamR cells by suppressing α6-integrin-Src-Akt signaling. In support of our hypothesis, TamR cells and associated mammospheres were found to exhibit elevated α6-integrin expression compared with their tamoxifen-sensitive counterparts. Furthermore, tumor sections from patients who relapsed on tamoxifen showed enhanced α6-integrin expression. Gene expression profiling from the TCGA database further revealed that basal-like breast cancer samples, known to be largely unresponsive to tamoxifen, demonstrated higher α6-integrin levels than luminal breast cancer samples. Importantly, AF reduced TamR cell viability and disrupted TamR mammospheres while concomitantly reducing α6-integrin messenger RNA and protein levels. In addition, AF and small interfering RNA against α6-integrin blocked tamoxifen-stimulated proliferation of TamR MCF-7 cells and further sensitized these cells to tamoxifen. Moreover, AF reduced Src and Akt signaling activation in TamR MCF-7 cells. Our findings suggest elevated α6-integrin expression is associated with tamoxifen resistance and AF suppresses α6-integrin-Src-Akt signaling activation to confer activity against TamR breast cancer.

The aryl hydrocarbon receptor (AhR) as a breast cancer drug target

“…Recent work demonstrated that AF inhibits the expression of α6‐integrin expression; the overexpression of these cell adhesion molecules is associated with tumor initiation cell proliferation, malignant breast cancer, and poor prognosis . Additionally, α6‐integrin overexpression is related to breast cancer resistance to radiotherapy, as well as tamoxifen resistance . AF reduces the expression of α6‐integrin in both tamoxifen‐resistant MCF‐7 and BT474 cells, inhibiting the α6‐integrin‐Src‐Akt signaling pathway, countering tamoxifen resistance in these ER‐positive cell lines …”

“…Additionally, α6‐integrin overexpression is related to breast cancer resistance to radiotherapy, as well as tamoxifen resistance . AF reduces the expression of α6‐integrin in both tamoxifen‐resistant MCF‐7 and BT474 cells, inhibiting the α6‐integrin‐Src‐Akt signaling pathway, countering tamoxifen resistance in these ER‐positive cell lines …”

Characterization of Glyceollins as Novel Aryl Hydrocarbon Receptor Ligands and Their Role in Cell Migration

“…Genistein can confer sensitivity to triple-negative breast cancer for antiestrogen therapy by preventing and reversing AhR-dependent BRCA1 hypermethylation [39]. Aminoflavone, another AhR ligand, inhibits the proliferation of tamoxifen-resistant cells by suppressing α6-integrin-Src-Akt signaling [40]. Raloxifene induces apoptosis mediated by AhR in ER-negative BC cells [41].…”

The Biological Functions and Clinical Applications of Integrins in Cancers

“…This result indicated that collagen/integrin β1/Src signal transduction was a key regulatory pathway that mediated the resistance of HER2 + breast cancer to anti-HER and anti-PI3K inhibitor combination therapy. In addition to integrin β1, another study found that activation of the integrin α6/Src/Akt signal transduction pathway mediated the resistance of breast cancer cells to tamoxifen ( Campbell et al., 2018 ). Upregulation of integrin α6 was found both in tamoxifen-resistant breast cancer cells and tumor tissue sections from patients who relapsed on tamoxifen treatment ( Campbell et al., 2018 ).…”