title: Genomic regulation of invasion by STAT3 in triple negative breast cancer.
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.
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.|The University of Alabama in Huntsville, Huntsville, AL 35899, USA.
authors.forename: Joy M
authors.initials: JM
authors.lastname: McDaniel
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Katherine E
authors.initials: KE
authors.lastname: Varley
authors.affiliation: Department of Oncological Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.
authors.forename: Jason
authors.initials: J
authors.lastname: Gertz
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Savic
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Brian S
authors.initials: BS
authors.lastname: Roberts
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Bailey
authors.affiliation: Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.|University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA.
authors.forename: Lalita A
authors.initials: LA
authors.lastname: Shevde
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.|Department of Genetics, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Ryne C
authors.initials: RC
authors.lastname: Ramaker
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Lasseigne
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Marie K
authors.initials: MK
authors.lastname: Kirby
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Kimberly M
authors.initials: KM
authors.lastname: Newberry
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: E Christopher
authors.initials: EC
authors.lastname: Partridge
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Angela L
authors.initials: AL
authors.lastname: Jones
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Braden
authors.initials: B
authors.lastname: Boone
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Shawn E
authors.initials: SE
authors.lastname: Levy
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Patsy G
authors.initials: PG
authors.lastname: Oliver
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA.
authors.forename: Katherine C
authors.initials: KC
authors.lastname: Sexton
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.affiliation: University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, AL 35294, USA.
authors.forename: Andres
authors.initials: A
authors.lastname: Forero
authors.affiliation: Department of Radiation Oncology, University of Alabama at Birmingham, Birmingham, AL, 35294, USA.
authors.forename: Donald J
authors.initials: DJ
authors.lastname: Buchsbaum
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Cooper
authors.affiliation: HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.
authors.forename: Richard M
authors.initials: RM
authors.lastname: Myers
mesh_terms: D045744:Cell Line, Tumor; D002465:Cell Movement; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011485:Protein Binding; D034622:RNA Interference; D050796:STAT3 Transcription Factor / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction; D059467:Transcriptome; D014162:Transfection; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human
keywords: ChIP-seq; RNA-seq; STAT3; TNBC; invasion