4.6 Article

DNA Methylation Predicts the Response of Triple-Negative Breast Cancers to All-Trans Retinoic Acid

Journal

CANCERS
Volume 10, Issue 11, Pages -

Publisher

MDPI
DOI: 10.3390/cancers10110397

Keywords

retinoic acid; triple-negative breast cancer; DNA methylation; biomarkers

Categories

Funding

  1. Canadian Institutes of Health Research (CIHR) [MOP-130304]
  2. Beatrice Hunter Cancer Research Institute (BHCRI)
  3. Breast Cancer Society of Canada
  4. QEII Health Sciences Centre Foundation
  5. CGS-D award from the CIHR
  6. Killam Trusts at Dalhousie University
  7. Dalhousie Medical Research Foundation
  8. Nova Scotia Health Research Foundation
  9. BHCRI
  10. Canadian Imperial Bank of Commerce
  11. CGS-M award from the CIHR

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All-trans retinoic acid (atRA) regulates gene expression and is used to treat acute promyelocytic leukemia. Attempts to use atRA in breast cancer without a stratification strategy have resulted in limited overall effectiveness. To identify biomarkers for the treatment of triple-negative breast cancer (TNBC) with atRA, we characterized the effects of atRA on the tumor growth of 13 TNBC cell lines. This resulted in a range of effects that was not predictable based on previously hypothesized predictors of response, such as the levels of atRA nuclear shuttling proteins fatty acid binding protein 5 (FABP5) and cellular retinoic acid binding protein 2 (CRABP2). Transcriptional profiling revealed that atRA induced distinct gene expression changes in the sensitive versus resistant cell lines that were mostly independent of the presence of retinoic acid response elements (RAREs) or peroxisome proliferator response elements (PPREs). Given the importance of DNA methylation in regulating gene expression, we hypothesized that differential DNA methylation could predict the response of TNBCs to atRA. We identified over 1400 sites that were differentially methylated between atRA resistant and sensitive cell lines. These CpG sites predicted the response of four TNBC patient-derived xenografts to atRA, and we utilized these xenografts to refine the profile and identified that as many as 17% of TNBC patients could benefit from atRA treatment. These data illustrate that differential methylation of specific CpGs may be useful biomarkers for predicting the response of patient tumors to atRA treatment.

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