Bisphenol-A induces expression of HOXC6, an estrogen-regulated homeobox-containing gene associated with breast cancer.
HOXC6 is a homeobox-containing gene associated with mammary gland development and is overexpressed in variety of cancers including breast and prostate cancers. Here, we have examined the expression of HOXC6 in breast cancer tissue, investigated its transcriptional regulation via estradiol (E2) and bisphenol-A (BPA, an estrogenic endocrine disruptor) in vitro and in vivo. We observed that HOXC6 is differentially over-expressed in breast cancer tissue. E2 induces HOXC6 expression in cultured breast cancer cells and in mammary glands of Sprague Dawley rats. HOXC6 expression is also induced upon exposure to BPA both in vitro and in vivo. Estrogen-receptor-alpha (ERα) and ER-coregulators such as MLL-histone methylases are bound to the HOXC6 promoter upon exposure to E2 or BPA and that resulted in increased histone H3K4-trimethylation, histone acetylation, and recruitment of RNA polymerase II at the HOXC6 promoter. HOXC6 overexpression induces expression of tumor growth factors and facilitates growth 3D-colony formation, indicating its potential roles in tumor growth. Our studies demonstrate that HOXC6, which is a critical player in mammary gland development, is upregulated in multiple cases of breast cancer, and is transcriptionally regulated by E2 and BPA, in vitro and in vivo.
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
Imran
I
Hussain
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
Arunoday
A
Bhan
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
Khairul I
KI
Ansari
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA.
Paromita
P
Deb
Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA.
Samara A M
SA
Bobzean
Department of Psychology, The University of Texas at Arlington, Arlington, TX 76019, USA.
Linda I
LI
Perrotti
Department of Chemistry and Biochemistry, The University of Texas at Arlington, Arlington, TX 76019, USA. Electronic address: smandal@uta.edu.
Subhrangsu S
SS
Mandal
D000818:Animals; D001559:Benzhydryl Compounds / Q000008:administration & dosage*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D052244:Endocrine Disruptors / Q000378:metabolism; D057890:Epigenomics; D004958:Estradiol / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000235:genetics; D004967:Estrogens / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D018398:Homeodomain Proteins / Q000096:biosynthesis* / Q000235:genetics; D006801:Humans; D061986:MCF-7 Cells; D010636:Phenols / Q000008:administration & dosage*; D051381:Rats; D000098826:Bisphenol A Compounds
D001559:Benzhydryl Compounds; D052244:Endocrine Disruptors; D004958:Estradiol; D047628:Estrogen Receptor alpha; D004967:Estrogens; D018398:Homeodomain Proteins; D010636:Phenols; C506487:ESR1 protein, human; C094289:HOXC6 protein, human; C006780:bisphenol A; D000098826:Bisphenol A Compounds
Bisphenol A; Endocrine disruption; Epigenetics; Estrogen-receptors; HOXC6 expression; Mixed lineage leukemia (MLL)