American Association for Cancer Research
00085472can122149-sup-fig3.pdf (660.78 kB)

Supplementary Figure 3 from Autocrine Motility Factor Promotes HER2 Cleavage and Signaling in Breast Cancer Cells

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journal contribution
posted on 2023-03-30, 21:45 authored by Dhong Hyo Kho, Pratima Nangia-Makker, Vitaly Balan, Victor Hogan, Larry Tait, Yi Wang, Avraham Raz

PDF file - 660K, Supplementary Figure S3. Secretion and expression of AMF is positively correlated with p185- and p95-HER2.



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. Cancer Res; 73(4); 1411–9. ©2012 AACR.

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