FGFR2 Signaling Provides an Alternate Mode of Her2/Neu Activation in Breast Cancer

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SUN 292-302-Breast & Prostate Cancer
Sunday, June 16, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SUN-297
Wangzhi Catherine Wei*1, Wei Liu1, Sylvia L. Asa2 and Shereen Z Ezzat1
1Ontario Cancer Institute, Toronto, ON, Canada, 2Univ Health Network, Toronto, ON, Canada
Background & Rationale: Her2/neu gene amplification and protein overexpression occur frequently in breast ductal carcinomas and correlate with aggressive malignant behavior and poor prognosis, but also provide a target for herceptin therapy. Distinct from other receptors of the ErbB family, Her2/neu lacks a dedicated cognate ligand, relying instead on hetero-dimerization with other members of the EGFR family. Insights into the complexity of combinatorial signals are important for elucidating the mechanisms of ErbB-induced mammary carcinogenesis. Fibroblast growth factor receptor 2 (FGFR2) has been identified in genome-wide association studies (GWAS) to be associated with increased breast cancer risk. We investigated the association between these two signaling families of RTKs.  

Methods & Results: Using the model of the Mouse Mammary Tumor Virus (MMTV) promoter-driven transgenic expression of Her2/neu we identified epithelial co-localization of Her2/neu and FGFR2 in resulting adenocarcinomas.  We also noted nuclear localization of Her2/neu in breast cancer MCF-7 cells that endogenously express the FGFR2-IIIb splice variant; an effect enhanced by the dedicated FGF ligand FGF7. Knockdown of FGFR2 in these cells was associated with attenuated Her2/neu nuclear translocation. Conversely, retroviral transduction of breast epithelial MCF-10A cells with or without FGFR2-IIIb and Her2/neu corroborated translocation of both oncoproteins from the plasma membrane into the nucleus under FGF7 control. The co-expression FGFR2 and Her2/neu resulted in enhanced STAT3 activation accompanied by EGF-independent cell proliferation. These actions were subject to Lapatinib-mediated pharmacologic inhibition consistent with the kinase requirement of Her2/neu.  

Conclusions & Future Prospects:  Our studies implicate a novel combination in the ErbB signalling network and demonstrate the synergistic interactions between the FGFR2 and Her2/neu susceptibility gene products in regulating cancer cell behaviour.  These data have potentially important therapeutic implications in the development of new targeting strategies for breast and other ErbB-dependent cancers.

Nothing to Disclose: WCW, WL, SLA, SZE

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Canadian Institutes of Health Research (CIHR)