Obesity‐induced MBD2_v2 expression promotes tumor‐initiating triple‐negative breast cancer stem cells

Abstract

Obesity is a risk factor for triple‐negative breast cancer ( TNBC ) incidence and poor outcomes, but the underlying molecular biology remains unknown. We previously identified in TNBC cell cultures that expression of epigenetic reader methyl‐CpG‐binding domain protein 2 ( MBD 2), specifically the alternative mRNA splicing variant MBD variant 2 ( MBD 2_v2), is dependent on reactive oxygen species ( ROS ) and is crucial for maintenance and expansion of cancer stem cell‐like cells ( CSC s). Because obesity is coupled with inflammation and ROS , we hypothesized that obesity can fuel an increase in MBD 2_v2 expression to promote the tumor‐initiating CSC phenotype in TNBC cells in vivo . Analysis of TNBC patient datasets revealed associations between high tumor MBD 2_v2 expression and high relapse rates and high body mass index ( BMI ). Stable gene knockdown/overexpression methods were applied to TNBC cell lines to elucidate that MBD 2_v2 expression is governed by ROS ‐dependent expression of serine‐ and arginine‐rich splicing factor 2 ( SRSF 2). We employed a diet‐induced obesity ( DIO ) mouse model that mimics human obesity to investigate whether obesity causes increased MBD 2_v2 expression and increased tumor initiation capacity in inoculated TNBC cell lines. MBD 2_v2 and SRSF 2 levels were increased in TNBC cell line‐derived tumors that formed more frequently in DIO mice relative to tumors in lean control mice. Stable MBD 2_v2 overexpression increased the CSC fraction in culture and increased TNBC cell line tumor initiation capacity in vivo . SRSF 2 knockdown resulted in decreased MBD 2_v2 expression, decreased CSC s in TNBC cell cultures, and hindered tumor formation in vivo . This report describes evidence to support the conclusion that MBD 2_v2 expression is induced by obesity and drives TNBC cell tumorigenicity, and thus provides molecular insights into support of the epidemiological evidence that obesity is a risk factor for TNBC . The majority of TNBC patients are obese and rising obesity rates threaten to further increase the burden of obesity‐linked cancers, which reinforces the relevance of this report.

Obesity and Cancer Metastasis: Molecular and Translational Perspectives

“…Furthermore, TNFα upregulates TAZ (a Hippo pathway effector) and Slug (an EMT mediator), which increase breast CSCs through both canonical and non-canonical NF-κB signaling [ 117 , 118 ]. Analysis of TNBC patient datasets reveals high tumor expression of the epigenetic reader methyl-CpG-binding domain protein 2 (MBD2), specifically the alternative splicing variant 2 (MBD2_v2) expression and high relapse rate and high BMI [ 119 ]. It is postulated that obesity drives high reactive oxygen species (ROS) levels, which subsequently promotes MBD2_v2 expression and an expansion of the CSC fraction [ 119 ].…”

<p>MBD2 Correlates with a Poor Prognosis and Tumor Progression in Renal Cell Carcinoma</p>

“…Aberrant DNA methylation modifications are frequently detected in various tumors, and the main mechanisms for DNA methylation-involved tumorigenesis are that methylation levels of the promoter region of anti-oncogene are elevated, which promotes the key anti-oncogene silencing and drives tumorigenesis. 12,[14][15][16] MBD2 has been reported in multiple human malignancies, including gastric cancer, 17 breast cancer, 18,19 colorectal cancer, 20 glioblastoma, 21,22 hilar cholangiocarcinoma, 23 hepatocellular carcinoma, 24,25 chronic myeloid leukemia 26 and prostate cancer. 27 Previous studies confirmed that MBD2 mediates the transcriptional repression of tumor suppressor genes, such as hTERT, 28 GSTP1, 29 BAI1, 21 p14 ARF /p16 INK4a,30 and 14-3-3sigma, 27 which supports the pivotal role of MBD2 in abnormal epigenetic regulation of tumors.…”

The Roles of DNA Demethylases in Triple-Negative Breast Cancer

“…TET1 expression was demonstrated to promote cell metastasis in colorectal cancer and activation of PI3K oncogenic signaling in TNBC. TET1 expression was shown to correlate with cell migration, cancer stemness tumorigenicity, and poor survivals in epithelial ovarian cancer and in TNBCs [ 77 , 78 , 79 ].…”