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Breast Cancer Research and Treatment

, Volume 151, Issue 3, pp 501–513 | Cite as

CD44 expression contributes to trastuzumab resistance in HER2-positive breast cancer cells

  • Delphine R. Boulbes
  • Gaurav B. Chauhan
  • Quanri Jin
  • Chandra Bartholomeusz
  • Francisco J. EstevaEmail author
Preclinical study

Abstract

Resistance to HER2-targeted therapies remains a major obstacle in the treatment of HER2-overexpressing breast cancer. CD44, a putative breast cancer stem cell (CSC) marker, is overexpressed in trastuzumab-resistant breast cancer cells. While CSC-related genes may play a role in the development of trastuzumab resistance, conflicting results have been published about CSC response to trastuzumab. We hypothesized that CD44 contributes to trastuzumab resistance independently of its role as a CSC marker. We used trastuzumab-sensitive breast cancer cell lines and their trastuzumab-resistant isogenic counterparts to evaluate the role of CD44 in response to trastuzumab. miRNA and mRNA expression were analyzed using microarray chips. A gene set enrichment analysis was created and matched with response to trastuzumab in cells and patient samples. The proportions of CSC in trastuzumab-resistant cells were similar to or lower than in the trastuzumab-sensitive cells. However, CD44 expression levels were significantly higher in both trastuzumab-resistant cell lines and its knockdown led to an increased response to trastuzumab. The invasiveness and anchorage-independent growth of trastuzumab-resistant cells were higher and blocked by downregulation of CD44. Results also showed that CD44-related resistance to trastuzumab is regulated by miRNAs. We identified a CD44-related gene expression profile that correlated with response to trastuzumab in cell lines and breast cancer patients. CD44 mediates trastuzumab resistance in HER2-positive breast cancer cells independently of its role as a CSC marker and that this role of CD44 is partly regulated by miRNA.

Keywords

CD44 Trastuzumab HER2 Breast cancer miRNA 

Abbreviations

CSC

Cancer stem cells

siRNA

Small interfering RNA

miRNA

MicroRNA

HER2

Human epidermal growth factor receptor 2

MUC4

Mucin-4

pCR

Pathologic complete response

RD

Residual disease

ES

Enrichment Score

NES

Normalized Enrichment Score

p-val

p value

FWER

Family-wise error rate

FDR

False discovery rate

Notes

Acknowledgments

This research was supported by the Breast Cancer Research Foundation (FJE). The University of Texas MD Anderson Cancer Center is supported in part by a Cancer Center Support Grant (CA016672) from the National Institutes of Health. The authors thank Xiaoping Su from Bioinformatics and Computational Biology for data analyses and Arthur Gelmis from the Department of Scientific Publications at MD Anderson Cancer Center for editorial assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

The experiments preformed in this manuscript comply with the current laws of the United States of America.

Supplementary material

10549_2015_3414_MOESM1_ESM.docx (14 kb)
Supplementary material 1 (DOCX 14 kb)
10549_2015_3414_MOESM2_ESM.pptx (693 kb)
Supplementary material 2 (PPTX 693 kb)

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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Delphine R. Boulbes
    • 1
  • Gaurav B. Chauhan
    • 1
  • Quanri Jin
    • 1
  • Chandra Bartholomeusz
    • 1
  • Francisco J. Esteva
    • 1
    • 2
    Email author
  1. 1.Departments of Breast Medical OncologyThe University of Texas MD Anderson Cancer CenterHoustonUSA
  2. 2.Division of Hematology-Oncology, Perlmutter Cancer CenterNew York University Langone Medical CenterNew YorkUSA

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