Gene expression analysis reveals distinct pathways of resistance to bevacizumab in xenograft models of human ER-positive breast cancer

Yesim Gökmen-Polar, Chirayu P. Goswami, Rachel A. Toroni, Kerry L. Sanders, Rutika Mehta, Usha Sirimalle, Bogdan Tanasa, Changyu Shen, Lang Li, Mircea Ivan, Sunil Badve, George W. Sledge

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Bevacizumab, the recombinant antibody targeting vascular endothelial growth factor (VEGF), improves progression-free but not overall survival in metastatic breast cancer. To seek further insights in resistance mechanisms to bevacizumab at the molecular level, we developed VEGF and non-VEGF driven ER-positive MCF-7 derived xenograft models allowing comparison of tumor response at different time-points. VEGF gene (MV165) overexpressing xenografts were initially sensitive to bevacizumab, but eventually acquired resistance. In contrast, parental MCF7 cells derived tumors were de novo insensitive to bevacizumab. Microarray analysis with qRT-PCR validation revealed that Follistatin (FST) and Notch were the top signaling pathways associated with resistance in VEGF-driven tumors (P<0.05). Based on the presence of VEGF, treatment with bevacizumab resulted in altered patterns of metagenes and PAM50 gene expression. In VEGF-driven model after short and long-term bevacizumab treatments, a change in the intrinsic subtype (luminal to myoepithelial/basal-like) was observed in association with increased expression of genes implicated with cancer stem cell phenotype (P<0.05). Our results show that the presence or absence of VEGF expression affects the response to bevacizumab therapy and gene pathways. In particular, long-term bevacizumab treatment shifts the cancer cells to a more aggressive myoepithelial/basal subtype in VEGF-expressing model, but not in non-VEGF model. These findings could shed light on variable results to anti-VEGF therapy in patients and emphasizes the importance of patient stratification based on the VEGF expression. Our data strongly suggest consideration of patient subgroups for treatment and designing novel combinatory therapies in the clinic setting.

Original languageEnglish (US)
Pages (from-to)633-645
Number of pages13
JournalJournal of Cancer
Volume5
Issue number8
DOIs
StatePublished - 2014

Keywords

  • Bevacizumab
  • Breast cancer
  • De novo and acquired resistance
  • Estrogen receptor
  • Vascular endothelial growth factor

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Gökmen-Polar, Y., Goswami, C. P., Toroni, R. A., Sanders, K. L., Mehta, R., Sirimalle, U., Tanasa, B., Shen, C., Li, L., Ivan, M., Badve, S., & Sledge, G. W. (2014). Gene expression analysis reveals distinct pathways of resistance to bevacizumab in xenograft models of human ER-positive breast cancer. Journal of Cancer, 5(8), 633-645. https://doi.org/10.7150/jca.8466