Genomic regulation of invasion by STAT3 in triple negative breast cancer

Abstract

// Joy M. McDaniel 1, 2 , Katherine E. Varley 3 , Jason Gertz 3 , Daniel S. Savic 1 , Brian S. Roberts 1 , Sarah K. Bailey 4 , Lalita A. Shevde 4, 6 , Ryne C. Ramaker 1, 7 , Brittany N. Lasseigne 1 , Marie K. Kirby 1 , Kimberly M. Newberry 1 , E. Christopher Partridge 1 , Angela L. Jones 1 , Braden Boone 1 , Shawn E. Levy 1 , Patsy G. Oliver 5 , Katherine C. Sexton 6 , William E. Grizzle 6 , Andres Forero 6 , Donald J. Buchsbaum 5 , Sara J. Cooper 1 , Richard M. Myers 1 1 HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA 2 The University of Alabama in Huntsville, Huntsville, AL 35899, USA 3 Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA 4 Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA 5 Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA 6 University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA 7 Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA Correspondence to: Richard M. Myers, email: rmyers@hudsonalpha.org Keywords: TNBC, STAT3, ChIP-seq, RNA-seq, invasion Received: August 15, 2016      Accepted: November 14, 2016      Published: December 24, 2016 ABSTRACT Breast cancer is a heterogeneous disease comprised of four molecular subtypes defined by whether the tumor-originating cells are luminal or basal epithelial cells. Breast cancers arising from the luminal mammary duct often express estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth receptor 2 (HER2). Tumors expressing ER and/or PR are treated with anti-hormonal therapies, while tumors overexpressing HER2 are targeted with monoclonal antibodies. Immunohistochemical detection of ER, PR, and HER2 receptors/proteins is a critical step in breast cancer diagnosis and guided treatment. Breast tumors that do not express these proteins are known as “triple negative breast cancer” (TNBC) and are typically basal-like. TNBCs are the most aggressive subtype, with the highest mortality rates and no targeted therapy, so there is a pressing need to identify important TNBC tumor regulators. The signal transducer and activator of transcription 3 (STAT3) transcription factor has been previously implicated as a constitutively active oncogene in TNBC. However, its direct regulatory gene targets and tumorigenic properties have not been well characterized. By integrating RNA-seq and ChIP-seq data from 2 TNBC tumors and 5 cell lines, we discovered novel gene signatures directly regulated by STAT3 that were enriched for processes involving inflammation, immunity, and invasion in TNBC. Functional analysis revealed that STAT3 has a key role regulating invasion and metastasis, a characteristic often associated with TNBC. Our findings suggest therapies targeting STAT3 may be important for preventing TNBC metastasis.