Endocrine disrupting chemical, bisphenol-A, induces breast cancer associated gene HOXB9 expression in vitro and in vivo

•HOXB9 is a homeobox containing gene associated with breast cancer.•HOXB9 expression is induced by estradiol (E2) in vitro and in vivo.•HOXB9 expression is also induced by endocrine disrupting chemical BPA.•ERs coordinate with MLLs during E2/BPA-induced HOXB9 expression.•Results provide mechanistic insight on HOXB9 gene regulation and its endocrine disruption.

HOXB9 is a homeobox-containing gene that plays a key role in mammary gland development and is associated with breast and other types of cancer. Here, we demonstrate that HOXB9 expression is transcriptionally regulated by estradiol (E2), in vitro and in vivo. We also demonstrate that the endocrine disrupting chemical bisphenol-A (BPA) induces HOXB9 expression in cultured human breast cancer cells (MCF7) as well as in vivo in the mammary glands of ovariectomized (OVX) rats. Luciferase assay showed that estrogen-response-elements (EREs) in the HOXB9 promoter are required for BPA-induced expression. Estrogen-receptors (ERs) and ER-co-regulators such as MLL-histone methylase (MLL3), histone acetylases, CBP/P300, bind to the HOXB9 promoter EREs in the presence of BPA, modify chromatin (histone methylation and acetylation) and lead to gene activation. In summary, our results demonstrate that BPA exposure, like estradiol, increases HOXB9 expression in breast cells both in vitro and in vivo through a mechanism that involves increased recruitment of transcription and chromatin modification factors.

Graphical abstractFigure optionsDownload full-size imageDownload high-quality image (171 K)Download as PowerPoint slide