title: AhR ligand Aminoflavone inhibits α6-integrin expression and breast cancer sphere-initiating capacity.
abstract: Traditional chemotherapies debulk tumors but fail to produce long-term clinical remissions due to their inability to eradicate tumor-initiating cells (TICs). This necessitates therapy with activity against the TIC niche. 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). We investigated the ability of AhR agonist Aminoflavone (AF) and AF pro-drug (AFP464) to disrupt mammospheres derived from breast cancer cells and a M05 mammary mouse model of breast cancer respectively. We further examined the capacity of AF and AFP464 to exhibit anticancer activity and modulate the expression of 'stemness' genes including α6-integrin using immunofluorescence, flow cytometry and 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 and AFP464 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 TIC growth via AhR agonist-mediated α6-integrin inhibition.
authors.affiliation: Department of Basic Sciences, Loma Linda University Health School of Medicine, 11021 Campus St, Alumni Hall Room 101, Loma Linda, CA 92354, USA; Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, USA.
authors.forename: Eileen
authors.initials: E
authors.lastname: Brantley
authors.affiliation: Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB Ciudad de Buenos Aires, Argentina.
authors.forename: Mariana A
authors.initials: MA
authors.lastname: Callero
authors.affiliation: Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB Ciudad de Buenos Aires, Argentina.
authors.forename: Damian E
authors.initials: DE
authors.lastname: Berardi
authors.affiliation: Department of Basic Sciences, Loma Linda University Health School of Medicine, 11021 Campus St, Alumni Hall Room 101, Loma Linda, CA 92354, USA.
authors.forename: Petreena
authors.initials: P
authors.lastname: Campbell
authors.affiliation: Department of Basic Sciences, Loma Linda University Health School of Medicine, 11021 Campus St, Alumni Hall Room 101, Loma Linda, CA 92354, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Rowland
authors.affiliation: Department of Pharmaceutical and Administrative Sciences, Loma Linda University Health School of Pharmacy, Loma Linda, CA, USA.
authors.forename: Dain
authors.initials: D
authors.lastname: Zylstra
authors.affiliation: Department of Basic Sciences, Loma Linda University Health School of Medicine, 11021 Campus St, Alumni Hall Room 101, Loma Linda, CA 92354, USA.
authors.forename: Louisa
authors.initials: L
authors.lastname: Amis
authors.affiliation: Division of Biomedical Sciences, School of Medicine, University of California, Riverside, CA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Yee
authors.affiliation: Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB Ciudad de Buenos Aires, Argentina.
authors.forename: Marina
authors.initials: M
authors.lastname: Simian
authors.affiliation: Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB Ciudad de Buenos Aires, Argentina.
authors.forename: Laura
authors.initials: L
authors.lastname: Todaro
authors.affiliation: Research Area, Institute of Oncology Ángel H. Roffo, University of Buenos Aires, Avenue San Martín 5481, C1417DTB Ciudad de Buenos Aires, Argentina. Electronic address: loaizaa2012@gmail.com.
authors.forename: Andrea I
authors.initials: AI
authors.lastname: Loaiza-Perez
authors.affiliation: Department of Basic Sciences, Loma Linda University Health School of Medicine, 11021 Campus St, Alumni Hall Room 101, Loma Linda, CA 92354, USA. Electronic address: usoto@llu.edu.
authors.forename: Ubaldo
authors.initials: U
authors.lastname: Soto
mesh_terms: D021581:Active Transport, Cell Nucleus; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D051792:Basic Helix-Loop-Helix Proteins / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039503:Integrin alpha6 / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D061986:MCF-7 Cells; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008807:Mice, Inbred BALB C; D014411:Neoplastic Stem Cells / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010641:Phenotype; D011355:Prodrugs / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D018874:Spheroids, Cellular; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D051792:Basic Helix-Loop-Helix Proteins; D005419:Flavonoids; D039503:Integrin alpha6; D008024:Ligands; D011355:Prodrugs; D018336:Receptors, Aryl Hydrocarbon; C111235:AHR protein, human; C484722:Ahr protein, mouse; C588002:ITGA6 protein, human; C413760:aminoflavone
keywords: Aminoflavone; Aryl hydrocarbon receptor; Mammospheres; α6-integrin