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

Petreena S. Campbell, Nicole Mavingire, Salma Khan, Leah K. Rowland, Jonathan V. Wooten, Anna Opoku-Agyeman, Ashley Guevara, Ubaldo Soto, Fiorella Cavalli, Andrea Irene Loaiza-Pérez, Gayathri Nagaraj, Laura J. Denham, Olayemi Adeoye, Brittany D. Jenkins, Melissa B Davis, Rachel Schiff, Eileen J. Brantley

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)108-121
Number of pages14
JournalJournal of Cellular Physiology
Volume234
Issue number1
DOIs
StatePublished - Jan 1 2018

Fingerprint

aminoflavone
Tamoxifen
Cells
Breast Neoplasms
Ligands
Integrins
Tumors
Neoplastic Stem Cells
Chemical activation
MCF-7 Cells

Keywords

  • AF
  • Src–Akt signaling
  • breast cancer
  • tamoxifen resistance
  • α6-integrin

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cell Biology

Cite this

Campbell, P. S., Mavingire, N., Khan, S., Rowland, L. K., Wooten, J. V., Opoku-Agyeman, A., ... Brantley, E. J. (2018). AhR ligand aminoflavone suppresses α6-integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells. Journal of Cellular Physiology, 234(1), 108-121. https://doi.org/10.1002/jcp.27013

AhR ligand aminoflavone suppresses α6-integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells. / Campbell, Petreena S.; Mavingire, Nicole; Khan, Salma; Rowland, Leah K.; Wooten, Jonathan V.; Opoku-Agyeman, Anna; Guevara, Ashley; Soto, Ubaldo; Cavalli, Fiorella; Loaiza-Pérez, Andrea Irene; Nagaraj, Gayathri; Denham, Laura J.; Adeoye, Olayemi; Jenkins, Brittany D.; Davis, Melissa B; Schiff, Rachel; Brantley, Eileen J.

In: Journal of Cellular Physiology, Vol. 234, No. 1, 01.01.2018, p. 108-121.

Research output: Contribution to journalArticle

Campbell, PS, Mavingire, N, Khan, S, Rowland, LK, Wooten, JV, Opoku-Agyeman, A, Guevara, A, Soto, U, Cavalli, F, Loaiza-Pérez, AI, Nagaraj, G, Denham, LJ, Adeoye, O, Jenkins, BD, Davis, MB, Schiff, R & Brantley, EJ 2018, 'AhR ligand aminoflavone suppresses α6-integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells', Journal of Cellular Physiology, vol. 234, no. 1, pp. 108-121. https://doi.org/10.1002/jcp.27013
Campbell, Petreena S. ; Mavingire, Nicole ; Khan, Salma ; Rowland, Leah K. ; Wooten, Jonathan V. ; Opoku-Agyeman, Anna ; Guevara, Ashley ; Soto, Ubaldo ; Cavalli, Fiorella ; Loaiza-Pérez, Andrea Irene ; Nagaraj, Gayathri ; Denham, Laura J. ; Adeoye, Olayemi ; Jenkins, Brittany D. ; Davis, Melissa B ; Schiff, Rachel ; Brantley, Eileen J. / AhR ligand aminoflavone suppresses α6-integrin–Src–Akt signaling to attenuate tamoxifen resistance in breast cancer cells. In: Journal of Cellular Physiology. 2018 ; Vol. 234, No. 1. pp. 108-121.
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