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HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.

Publication ,  Journal Article
Hartman, ZC; Yang, X-Y; Glass, O; Lei, G; Osada, T; Dave, SS; Morse, MA; Clay, TM; Lyerly, HK
Published in: Cancer Res
July 1, 2011

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.

Duke Scholars

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Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2011

Volume

71

Issue

13

Start / End Page

4380 / 4391

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mice, SCID
  • Mice, Inbred NOD
 

Citation

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MLA
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Hartman, Z. C., Yang, X.-Y., Glass, O., Lei, G., Osada, T., Dave, S. S., … Lyerly, H. K. (2011). HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res, 71(13), 4380–4391. https://doi.org/10.1158/0008-5472.CAN-11-0308
Hartman, Zachary C., Xiao-Yi Yang, Oliver Glass, Gangjun Lei, Takuya Osada, Sandeep S. Dave, Michael A. Morse, Timothy M. Clay, and Herbert K. Lyerly. “HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.Cancer Res 71, no. 13 (July 1, 2011): 4380–91. https://doi.org/10.1158/0008-5472.CAN-11-0308.
Hartman ZC, Yang X-Y, Glass O, Lei G, Osada T, Dave SS, et al. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 2011 Jul 1;71(13):4380–91.
Hartman, Zachary C., et al. “HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis.Cancer Res, vol. 71, no. 13, July 2011, pp. 4380–91. Pubmed, doi:10.1158/0008-5472.CAN-11-0308.
Hartman ZC, Yang X-Y, Glass O, Lei G, Osada T, Dave SS, Morse MA, Clay TM, Lyerly HK. HER2 overexpression elicits a proinflammatory IL-6 autocrine signaling loop that is critical for tumorigenesis. Cancer Res. 2011 Jul 1;71(13):4380–4391.

Published In

Cancer Res

DOI

EISSN

1538-7445

Publication Date

July 1, 2011

Volume

71

Issue

13

Start / End Page

4380 / 4391

Location

United States

Related Subject Headings

  • Up-Regulation
  • Transcription Factors
  • Signal Transduction
  • STAT3 Transcription Factor
  • Receptor, erbB-2
  • Receptor, ErbB-2
  • Phosphorylation
  • Oncology & Carcinogenesis
  • Mice, SCID
  • Mice, Inbred NOD