Autocrine motility factor promotes HER2 cleavage and signaling in breast cancer cells.

Abstract

Trastuzumab (Herceptin) is an effective targeted therapy in HER2-overexpressing human breast carcinoma. However, many HER2-positive patients initially or eventually become resistant to this treatment, so elucidating mechanisms of trastuzumab resistance that emerge in breast carcinoma cells is clinically important. Here, we show that autocrine motility factor (AMF) binds to HER2 and induces cleavage to the ectodomain-deleted and constitutively active form p95HER2. Mechanistic investigations indicated that interaction of AMF with HER2 triggers HER2 phosphorylation and metalloprotease-mediated ectodomain shedding, activating phosphoinositide-3-kinase (PI3K) and mitogen-activated protein kinase signaling and ablating the ability of trastuzumab to inhibit breast carcinoma cell growth. Furthermore, we found that HER2 expression and AMF secretion were inversely related in breast carcinoma cells. On the basis of this evidence that AMF may contribute to HER2-mediated breast cancer progression, our findings suggest that AMF-HER2 interaction might be a novel target for therapeutic management of patients with breast cancer, whose disease is resistant to trastuzumab.

• Authors: Dhong Hyo Kho, Pratima Nangia-Makker, Vitaly Balan, Victor Hogan, Larry Tait, Yi Wang, Avraham Raz
• Journal: Cancer research (Cancer Res) Vol. 73 Issue 4 Pg. 1411-9 (Feb 15 2013) ISSN: 1538-7445 [Electronic] United States
• PMID: 23248119 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents
• AMFR protein, human
• Receptors, Autocrine Motility Factor
• Phosphatidylinositol 3-Kinases
• Receptor, ErbB-2
• Mitogen-Activated Protein Kinases
• Glucose-6-Phosphate Isomerase
• Trastuzumab

Topics

• Antibodies, Monoclonal, Humanized (pharmacology)
• Antineoplastic Agents (pharmacology)
• Blotting, Western
• Breast Neoplasms (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Drug Resistance, Neoplasm
• Enzyme Activation (drug effects)
• Female
• Glucose-6-Phosphate Isomerase (genetics, metabolism, pharmacology)
• HEK293 Cells
• Humans
• Mitogen-Activated Protein Kinases (metabolism)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphorylation (drug effects)
• Protein Binding
• RNA Interference
• Receptor, ErbB-2 (genetics, metabolism)
• Receptors, Autocrine Motility Factor (genetics, metabolism)
• Signal Transduction
• Trastuzumab