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FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

ABSTRACT: Background: Triple negative breast cancers are aggressive, enriched with cancer stem cells, and lack effective targeted therapies with little side effects. Methods: We isolated cancer stem cells from two triple negative breast cancer cell lines via cell sorting following transcriptome sequencing, bioinformatics analysis, experimental and clinical validations, as well as functional investigations to explore genes capturing triple negative breast cancer features for improved diagnosis and therapeutics in clinics. Results: We found that FA2H is under-expressed in triple negative breast cancers both in vitro and in clinics, and FA2H suppresses cancer stemness via inhibiting the STAT3/IL6 axis and NFkB signaling. Conclusions: This study reports the tumor suppressive roles of FA2H on breast cancer cells through cancer stemness control. FA2H and other candidates unveiled in this study that capture the features of cancer stem cells may contribute as diagnostic marker and/or effective therapeutic targets for improved triple negative breast cancer management.

SUBMITTER: Dai X

PROVIDER: S-EPMC6821679 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

Dai Xiaofeng X Zhang Shuo S Cheng Hongye H Cai Dongyan D Chen Xiao X Huang Zhaohui Z

Frontiers in oncology 20191024

<b>Background:</b> Triple negative breast cancers are aggressive, enriched with cancer stem cells, and lack effective targeted therapies with little side effects. <b>Methods:</b> We isolated cancer stem cells from two triple negative breast cancer cell lines via cell sorting following transcriptome sequencing, bioinformatics analysis, experimental and clinical validations, as well as functional investigations to explore genes capturing triple negative breast cancer features for improved diagnosi ...[more]

PMID: 31709178

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Project description:The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells.Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines.Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple-negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB-468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in the expression of the microRNAs.This study provides evidence of posttranscriptional downregulation of Smurf2 in triple-negative breast cancers, and demonstrates that the loss of RB function is involved in microRNA-mediated interference with Smurf2 translation. The new link from RB inactivation to Smurf2 downregulation is likely to play a role in malignant phenotypes of triple-negative breast cancer cells.

Dataset Information

FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

Publications

FA2H Exhibits Tumor Suppressive Roles on Breast Cancers via Cancer Stemness Control.

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