title: HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.
abstract: HER2 overexpression occurs in approximately 25% of breast cancers, where it correlates with poor prognosis. Likewise, systemic inflammation in breast cancer correlates with poor prognosis, although the process is not understood. In this study, we explored the relationship between HER2 and inflammation, comparing the effects of overexpressing wild-type or mutated inactive forms of HER2 in primary human breast cells. Wild-type HER2 elicited a profound transcriptional inflammatory profile, including marked elevation of interleukin-6 (IL-6) expression, which we established to be a critical determinant of HER2 oncogenesis. Mechanistic investigations revealed that IL-6 secretion induced by HER2 overexpression activated Stat3 and altered gene expression, enforcing an autocrine loop of IL-6/Stat3 expression. Both mouse and human in vivo models of HER2-amplified breast carcinoma relied critically on this HER2-IL-6-Stat3 signaling pathway. Our studies offer the first direct evidence linking HER2 to a systemic inflammatory mechanism that orchestrates HER2-mediated tumor growth. We suggest that the HER2-IL-6-STAT3 signaling axis we have defined in breast cancer could prompt new therapeutic or prevention strategies for treatment of HER2-amplified cancers.
authors.affiliation: Duke Comprehensive Cancer Center, Department of Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. ZHartman@mdanderson.org
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Hartman
authors.forename: Xiao-Yi
authors.initials: XY
authors.lastname: Yang
authors.forename: Oliver
authors.initials: O
authors.lastname: Glass
authors.forename: Gangjun
authors.initials: G
authors.lastname: Lei
authors.forename: Takuya
authors.initials: T
authors.lastname: Osada
authors.forename: Sandeep S
authors.initials: SS
authors.lastname: Dave
authors.forename: Michael A
authors.initials: MA
authors.lastname: Morse
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Clay
authors.forename: Herbert K
authors.initials: HK
authors.lastname: Lyerly
mesh_terms: D016475:3T3 Cells; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007249:Inflammation / Q000378:metabolism; D015850:Interleukin-6 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008807:Mice, Inbred BALB C; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015850:Interleukin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D014157:Transcription Factors