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

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.

• Authors: Sabine M Brouxhon, Stephanos Kyrkanides, Xiaofei Teng, M Kerry O'Banion, Robert Clarke, Stephen Byers, Li Ma
• Journal: Molecular carcinogenesis (Mol Carcinog) Vol. 53 Issue 11 Pg. 893-906 (Nov 2014) ISSN: 1098-2744 [Electronic] United States
• PMID: 23776059 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2013 Wiley Periodicals, Inc.

Chemical References

• Cadherins
• MTOR protein, human
• Phosphatidylinositol 3-Kinase
• EGFR protein, human
• ERBB2 protein, human
• ERBB3 protein, human
• ErbB Receptors
• Receptor, ErbB-2
• Receptor, ErbB-3
• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases

Topics

• Aged
• Animals
• Cadherins (antagonists & inhibitors, metabolism, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• ErbB Receptors (biosynthesis, metabolism)
• Female
• Humans
• MCF-7 Cells
• Mice
• Middle Aged
• Molecular Targeted Therapy
• Neoplasm Invasiveness
• Phosphatidylinositol 3-Kinase (biosynthesis)
• Proto-Oncogene Proteins c-akt (biosynthesis)
• Receptor, ErbB-2 (biosynthesis, metabolism)
• Receptor, ErbB-3 (biosynthesis, metabolism)
• Signal Transduction
• TOR Serine-Threonine Kinases (biosynthesis)
• Triple Negative Breast Neoplasms (drug therapy, metabolism, pathology)