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J Cell Physiol. 2018 Jan;234(1):108-121. doi: 10.1002/jcp.27013. Epub 2018 Aug 4.

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

Author information

1
Department of Basic Sciences, Loma Linda University Health School of Medicine, Loma Linda, California.
2
Área de Investigaciónes, Universidad de Buenos Aires, Instituto de Oncología "Ángel H. Roffo," Ciudad Autónoma de Buenos Aires, Ciudad Autónoma de Buenos Aires, Argentina.
3
Department of Medicine, Loma Linda University Health School of Medicine, Loma Linda, California.
4
Department of Pathology, Loma Linda University Health School of Medicine, Loma Linda, California.
5
Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, California.
6
Department of Public Health Sciences, Henry Ford Cancer Institute, Detroit, Michigan.
7
Department of Molecular and Cellular Biology, Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.
8
Department of Medicine, Lester and Sue Smith Breast Center, Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas.

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.

KEYWORDS:

AF; Src-Akt signaling; breast cancer; tamoxifen resistance; α6-integrin

PMID:
30076704
PMCID:
PMC6202151
[Available on 2019-08-04]
DOI:
10.1002/jcp.27013

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