AhR ligand Aminoflavone inhibits α6- integrin expression and breast cancer sphere-initiating capacity

BRANTLEY; CALLERO; BERARDI; CAMPBELL; ROWLAND; ZYLSTRA; AMIS; YEE; SIMIAN; TODARO; LOAIZA PEREZ; SOTO

CANCER LETTERS

ELSEVIER IRELAND LTD

Lugar: Amsterdam; Año: 2016 vol. 376 p. 53 - 61

0304-3835

Traditional chemotherapies debulk tumors but fail to produce long-term clinical remissions due to theirinability to eradicate tumor-initiating cells (TICs). This necessitates therapy with activity against the TICniche. Αlpha6-integrin (α6-integrin) promotes TIC growth. In contrast, aryl hydrocarbon receptor (AhR)signaling activation impedes the formation of mammospheres (clusters of cells enriched for TICs). Weinvestigated the ability of AhR agonist Aminoflavone (AF) and AF pro-drug (AFP464) to disruptmammospheres derived from breast cancer cells and a M05 mammary mouse model of breast cancerrespectively.We further examined the capacity of AF and AFP464 to exhibit anticancer activity and modulatethe expression of ?stemness? genes including α6-integrin using immunofluorescence, flow cytometryand qRT-PCR analysis. AF disrupted mammospheres and prevented secondary mammosphere formation.In contrast, AF did not disrupt mammospheres derived from AhR ligand-unresponsive MCF-7 cells.AFP464 treatment suppressed M05 tumor growth and disrupted corresponding mammospheres. AF andAFP464 reduced the expression and percentage of cells that stained for ?stemness? markers including α6-integrin in vitro and in vivo respectively. These data suggest AFP464 thwarts bulk breast tumor and TICgrowth via AhR agonist-mediated α6-integrin inhibition