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

Abstract

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.

ALDH1A3-regulated long non-coding RNA NRAD1 is a potential novel target for triple-negative breast tumors and cancer stem cells

“…Error bars represent standard deviation (n.d. = not detected) associated with poor prognosis, actively promotes tumor growth, invasion, and metastasis, contributes to chemoresistance in multiple cancers, and has been proposed as a therapeutic target [23, 25, 27-31, 36, 61-70]. ALDH1A3's tumor-promoting activities are in part mediated by its generation of retinoic acid and subsequent gene expression changes; [27,71] however, it is unclear which are ALD-H1A3's key downstream oncogenic effectors. Identifying these effectors would delineate the mechanism of ALDH1A3 in cancer.…”

Retinoic Acids in the Treatment of Most Lethal Solid Cancers

“…It was also reported that KLF2 suppresses the expression of FABP5 in MCF-7 cell line [78]. However, a recent paper found conflicting result related to FABP5/CRABPII ratio implication on ATRA sensitivity in triple-negative breast cancer [79], so that further data are needed, especially for other solid cancer types than breast.…”

“…Following the studies that highlighted the retinoic acids' activity in suppressing the growth of different cancer cell lines, some studies focused on the genes expressed after the retinoid acids' treatment as probably tumor suppressor genes. A recent paper of Coyle and colleagues found that between 13 triple-negative breast cancer cell lines, 1400 sites were differentially methylated between ATRA resistant and sensitive cell lines [79]. Considering that the retinoic acids can activate the transcription factors that exert their action by biding to the RARE present on the promoter of the retinoid-responsive genes, impaired transcription on these genes might determine the retinoid acids' resistance.…”

All-Trans Retinoic Acid Stimulates Viral Mimicry, Interferon Responses and Antigen Presentation in Breast-Cancer Cells

“…A large mass of pre-clinical data indicates that ATRA is a promising agent in the prevention/treatment of breast cancer [5][6][7]. Breast cancer (BC) is a very heterogeneous disease [8] which is traditionally classified in three major groups for clinical purposes, i.e., estrogen-receptor-positive (ER + ), HER2-positive (HER2 + ) and triple-negative (TNBC).…”