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HER2 Overexpression Triggers an IL1a Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance
  • 작성일2019-05-09
  • 최종수정일2019-05-09
  • 담당부서연구기획과
  • 연락처043-719-8033
  • 1,128
Cancer Research, 2018, 78(8), 2040─2051, DOI: https://doi.org/10.1158/0008-5472.CAN-17-2761

HER2 Overexpression Triggers an IL1a Proinflammatory Circuit to Drive Tumorigenesis and Promote Chemotherapy Resistance

Shou Liu, Ji Shin Lee; Chunfa Jie; Min Ho Park;Yoichiro Iwakura;Yogin Patel; Mithil Soni; David Reisman; Hexin Chen

Abstract

    Systemic inflammation in breast cancer correlates with poor prognosis, but the molecular underpinnings of this connection are not well understood. In this study, we explored the relationship between HER2 overexpression, inflammation, and expansion of the mammary stem/progenitor and cancer stem–like cell (CSC) population in breast cancer. HER2-positive epithelial cells initiated and sustained an inflammatory milieu needed to promote tumorigenesis. HER2 induced a feedforward activation loop of IL1a and IL6 that stimulated NFkB and STAT3 pathways for generation and maintenance of breastCSC. In mice, Il1a genetic deficiency delayed MMTV-Her2–induced tumorigenesis and reduced inflammatory cytokine expression as well as CSC in primary tumors. In clinical specimens of human breast tumor tissues, tissue microarray analysis revealed a strong positive correlation between IL1a/IL6 expression andCSC-positivephenotype. Pharmacologic blockade of IL1a signaling reduced the CSC population and improved chemotherapeutic efficacy.Ourfindings suggest newtherapeutic or prevention strategies for HER2-positive breast cancers. Significance: IL1a signaling driven by HER2 promotes chronic inflammation needed to support cancer stem-like cell maintenance in HER2-positive breast cancers.



  • 본 연구는 질병관리본부 연구개발과제(과제번호 2018-보건의료생물자원종합관리) 연구비를 지원받아 수행되었습니다.
  • This research was supported by a fund(code 2018-보건의료생물자원종합관리) by Research of Korea Centers for Disease Control and Prevention.


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