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

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

Molecular carcinogenesis (2013-06-19)
Sabine M Brouxhon, Stephanos Kyrkanides, Xiaofei Teng, M Kerry O'Banion, Robert Clarke, Stephen Byers, Li Ma
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
5-Bromo-2′-deoxyuridine, BioUltra, ≥99%
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥99.0% (T)
Sigma-Aldrich
Phenylmethanesulfonyl fluoride, ≥98.5% (GC)
Sigma-Aldrich
E-Cadherin human, recombinant, expressed in E. coli, 0.5 mg protein/mL
Sigma-Aldrich
EGF human, Animal-component free, recombinant, expressed in E. coli, ≥98% (SDS-PAGE), ≥98% (HPLC), suitable for cell culture
Sigma-Aldrich
hEGF, EGF, recombinant, expressed in E. coli, lyophilized powder, suitable for cell culture
Sigma-Aldrich
Epidermal Growth Factor, human, animal component free, EGF, recombinant, expressed in Escherichia coli, >97% (SDS-PAGE)