Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers

Sabine M. Brouxhon, Stephanos Kyrkanides, Xiaofei Teng, M. Kerry O'Banion, Robert Clarke, Stephen Byers, Li Ma

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Recent literature suggests that sEcad exerts pro-oncogenic effects, possibly acting as a ligand for the human epidermal growth factor family. Here we show that sEcad is a novel candidate protein for drug targeting since it is increased in human and mouse HER2-positive (HER2+) breast tumors, MMTV-PyMT bodily fluids and human cell culture systems. Mechanistically, we show that endogenous sEcad, and to a lesser extent membrane-bound E-cadherin, associates with HER1, HER2, and HER3 in human and MMTV-PyMT mouse HER2+ tumors and with HER1 in triple negative breast cancer (TNBC) specimens. Furthermore, addition of exogenous recombinant human E-cadherin/Fc chimeric protein (rhEcad/Fc; sEcad) to HER2+ MCF-7, SKBR3, and HER2-negative MDA-MB-231 TNBC cells, resulted in sEcad-HER receptor family interactions, activation of HER1-4 and downstream pro-survival signaling, including the MAPK-PI3K/Akt/mTOR pathways and IAP family members. Lastly, we demonstrate that sEcad exerts pro-oncogenic effects via HER signaling, and acts additively with the HER ligand EGF to promote HER2+ breast cancer proliferation and migration, as well as TNBC invasion. Because sEcad associates and activates many of the oncogenic pathways that tumors utilize for growth and survival and serum levels in patients correlates with clinical response, suggests that targeted therapy against sEcad in combination with other therapies may potentially offer a novel therapeutic strategy for the treatment of breast cancers.

Original languageEnglish (US)
Pages (from-to)893-906
Number of pages14
JournalMolecular Carcinogenesis
Volume53
Issue number11
DOIs
StatePublished - Nov 1 2014
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2013 Wiley Periodicals, Inc.

Keywords

  • Akt
  • HER1-4
  • IAPs
  • MTOR
  • PI3K
  • SEcad

Fingerprint

Dive into the research topics of 'Soluble-E-cadherin activates HER and IAP family members in HER2+ and TNBC human breast cancers'. Together they form a unique fingerprint.

Cite this