Effects of HER2 overexpression on cell signaling networks governing proliferation and migration

Abstract

Although human epidermal growth factor receptor 2 (HER2) overexpression is implicated in tumor progression for a variety of cancer types, how it dysregulates signaling networks governing cell behavioral functions is poorly understood. To address this problem, we use quantitative mass spectrometry to analyze dynamic effects of HER2 overexpression on phosphotyrosine signaling in human mammary epithelial cells stimulated by epidermal growth factor (EGF) or heregulin (HRG). Data generated from this analysis reveal that EGF stimulation of HER2-overexpressing cells activates multiple signaling pathways to stimulate migration, whereas HRG stimulation of these cells results in amplification of a specific subset of the migration signaling network. Self-organizing map analysis of the phosphoproteomic data set permitted elucidation of network modules differentially regulated in HER2-overexpressing cells in comparison with parental cells for EGF and HRG treatment. Partial least-squares regression analysis of the same data set identified quantitative combinations of signals within the networks that strongly correlate with cell proliferation and migration measured under the same battery of conditions. Combining these modeling approaches enabled association of epidermal growth factor receptor family dimerization to activation of specific phosphorylation sites, which appear to most critically regulate proliferation and/or migration.

2D-DIGE analysis of phospho-enriched fractions from dasatinib-treated melanoma cell lines

“…No phosphorylation events were identified in this region of the protein (232-245) in either spot 26 or 27; however, this peptide sequence was not detected in the analysis of spot 29. Phosphory-lation of Y236 has been previously associated with migration [24]. The exact site of the phosphorylation was not established during our analysis.…”

Association of ERBB2 gene status with histopathological parameters and disease-specific survival in gastric carcinoma patients

“…Our survival analysis showed that ERBB2-amplifying expansive carcinomas have worse prognosis than those with the same growth pattern lacking that genetic alteration (P ¼ 0.011), which we did not observe in infiltrating gastric carcinomas (P ¼ 0.863). Recent data published by Wolf-Yadlin et al (2006) might explain the different effect of ERBB2 amplification in carcinomas with different growth patterns. These authors suggested that ERBB2 overexpression promotes increased cell migration but has minimal effect on cell proliferation in cells stimulated by epidermal growth factor or heregulin (Wolf-Yadlin et al, 2006).…”

“…Recent data published by Wolf-Yadlin et al (2006) might explain the different effect of ERBB2 amplification in carcinomas with different growth patterns. These authors suggested that ERBB2 overexpression promotes increased cell migration but has minimal effect on cell proliferation in cells stimulated by epidermal growth factor or heregulin (Wolf-Yadlin et al, 2006). Thus, ERBB2 amplification could increase cell migration in expansive carcinomas, whereas infiltrative carcinomas, which already have a strong invasive potential, do not acquire additional advantage from ERBB2 amplification.…”

Progressive loss of anti-HER2 CD4+ T-helper type 1 response in breast tumorigenesis and the potential for immune restoration

“…2 HER2 overexpression, a molecular oncodriver in several tumor types including 20-25% of BCs, 3 is associated with an aggressive clinical course, resistance to chemotherapy, and a poor overall prognosis. 4,5 In incipient BC, HER2 overexpression is associated with enhanced invasiveness, 6 tumor cell migration, 7 and the expression of proangiogenic factors, 8 suggesting a critical role for HER2 in promoting a tumorigenic environment. Although HER2-targeted therapies (i.e., trastuzumab), in combination with chemotherapy, have significantly improved survival in HER2 pos BC, 9 a substantial proportion of patients become resistant to such therapies.…”