Abstract P2-04-01: The role of Jmjd1a in mammary gland development and breast tumor growth

Abstract

Abstract Histone modification alters chromatin architecture and thereby influences gene transcription. Histone methylation status is reversible and counter-regulated by methyltransferases and demethylases. Jmjd1a (also known as KDM3A, TSGA, JMJD1, JHDM2A and JHMD2A) is a histone demethylase. It belongs to JmjC domain-containing protein family and could specifically remove di- and mono- methyl residues from di or mono-methylated histone H3K9 (H3K9me2/me1). Recent studies showed that Jmjd1a plays an important role in embryonic stem cell self-renewal, spermatogenesis, regulation of metabolic gene expression and body weight, sex determination, tumor angiogenesis, and macrophage infiltration. However, its role in mammary gland (MG) development, breast carcinogenesis and breast cancer progression hasn't been systemically investigated. In this study, we found that Jmjd1a is expressed in mouse luminal epithelial cells. Genetic disruption of the Jmjd1a gene significantly slowed down MG development as indicated by retarded MG elongation and decreased ductal density in virgin mice observed at the ages of 4, 6 and 8 weeks. In agreement with the retarded MG development, the expression of Ki67 and cyclinD1 in epithelial cells of MGs from Jmjd1a knockout (KO) mice dramatically reduced compared with that from wild type (WT) mice. H3K9me1 and H3K9me2 levels in the epithelial cells of KO MGs are much higher than that in WT MGs. To assess the role of Jmjd1a in breast cancer progression, we crossbred Tg(Jmjd1a-/-) mice with MMTV-TVA(RCAS-PyMT) mice and obtained Tg(Jmjd1a-/-)×MMTV-TVA(RCAS-PyMT) mice. Infection of the TVA-expressing MG epithelial cells with the RCAS-PyMT virus induced mammary tumors in these mice and MMTV-TVA(RCAS-PyMT) control mice. We found that KO of Jmjd1a slightly accelerated mammary tumor initiation but significantly decreased tumor growth. Ki67 and cyclinD1 expression statistically reduced in KO tumors versus WT tumors. At the molecular level, Jmjd1a expression positively correlated with cyclin D1 expression in mammary epithelial cells and mammary tumors. Knockdown of Jmjd1a in MCF-7 cells significantly reduced cyclin D1 expression, while ectopic expression of Jmjd1a in MCF-7 cells increased cyclin D1 expression. ChIP assay revealed that Jmjd1a is associated with a promoter region of cyclin D1. Co-expression of c-Myc and Jmjd1a boosted the activity of the cyclin D1 reporter. In conclusion, our study indicated that Jmjd1a plays an important role in promoting mammary gland development and breast tumor growth by up-regulating cyclin D1 expression. Targeting Jmjd1a may inhibit breast cancer progression. Citation Format: Qin L, Xu Y, Wu Y, Yu X, Toneff MJ, Liao L, Li Y, Xu J. The role of Jmjd1a in mammary gland development and breast tumor growth. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-04-01.