Gene Expression Analysis Reveals Distinct Pathways of Resistance to Bevacizumab in Xenograft Models of Human ER-Positive Breast Cancer

• Type of Material: Article
• Authors: Yesim Polar, Emory University; Chirayu P. Goswami, Indiana University; Rachel A. Toroni, Indiana University; Kerry L. Sanders, Indiana University; Rutika Mehta, Indiana University; Usha Sirimalle, Indiana University; Bogdan Tanasa, University of Medicine and Pharmacy; Changyu Shen, Indiana University; Lang Li, Indiana University; Mircea Ivan, Indiana University; Sunil Badve, Emory University; George W. Sledge, Jr., Indiana University
• Language: English
• Date: 2014-01-01
• Publisher: IVYSPRING INT PUBL
• Publication Version: Final Published Version
• Copyright Statement: © Ivyspring International Publisher.
• License: Creative Commons Attribution-NonCommerical-NoDerivs 3.0 Unported
• Final Published Version (URL): http://dx.doi.org/10.7150/jca.8466
• Title of Journal or Parent Work: JOURNAL OF CANCER
• Volume: 5
• Issue: 8
• Start Page: 633
• End Page: 645
• Grant/Funding Information: This work was supported by Breast Cancer Research Foundation grant to George W. Sledge, Jr.
• Keywords: ANTI-VEGF THERAPY; Science & Technology; PACLITAXEL PLUS BEVACIZUMAB; vascular endothelial growth factor; ACTIVIN; PROGNOSTIC-SIGNIFICANCE; ENDOTHELIAL GROWTH-FACTOR; breast cancer; CELLS; estrogen receptor; Bevacizumab; FGF; ANGIOGENESIS; Oncology; Life Sciences & Biomedicine; de novo and acquired resistance; TUMOR-GROWTH; PROGRESSION
• Research Categories: Health Sciences, Oncology; Biology, Cell

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. © Ivyspring International Publisher.