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Phytosphingosine exhibits an anti-epithelial-mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells.

ABSTRACT: The lack of effective anti-metastatic drugs for the eradication of breast cancer stem cells within tumors, which are often resistant to chemotherapy and radiotherapy, creates a major obstacle during metastatic breast cancer therapy. Although D-ribo-phytosphingosine (PHS) is well known to activate protein kinase (MAPK)-mediated apoptosis, its possible role towards the metastasis signaling mechanisms underlying the epithelial-mesenchymal transition (EMT) remains largely unknown. In this report, we investigate the anti-metastatic potential of the natural sphingolipid PHS for the targeting of breast cancer cells as well as breast stem-like cells in vitro. We showed that PHS led to suppression of migratory potential, spheroid formation, CD44high/CD24low subpopulation as well as stem cell- and EMT-associated protein expression in basal type highly malignant breast cancer cell lines. In addition, PHS-based inhibition of EMT was attributable to the downregulation of the EGFR/JAK1/STAT3 signaling axis, as validated by immunoprecipitation assays and breast tumorigenesis mice models. This study demonstrate that PHS can target metastatic tumors with dual specificity (EMT and cancer stem-like cells) and therefore may be serve as a promising candidate for breast cancer treatments.

SUBMITTER: Kang HM

PROVIDER: S-EPMC5649924 | biostudies-literature | 2017 Sep

REPOSITORIES: biostudies-literature

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Phytosphingosine exhibits an anti-epithelial-mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells.

Kang Hye-Min HM Son Han-Sun HS Cui Yan-Hong YH Youn BuHyun B Son Beomseok B Kaushik Nagendra Kumar NK Uddin Nizam N Lee Jae-Seong JS Song Jie-Young JY Kaushik Neha N Lee Su-Jae SJ

Oncotarget 20170908 44

The lack of effective anti-metastatic drugs for the eradication of breast cancer stem cells within tumors, which are often resistant to chemotherapy and radiotherapy, creates a major obstacle during metastatic breast cancer therapy. Although D-ribo-phytosphingosine (PHS) is well known to activate protein kinase (MAPK)-mediated apoptosis, its possible role towards the metastasis signaling mechanisms underlying the epithelial-mesenchymal transition (EMT) remains largely unknown. In this report, we ...[more]

PMID: 29100426

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Project description:Epithelial to mesenchymal transition (EMT) is associated with the basal-like breast cancer phenotypes. 60% of basal-like cancers have been shown to express wild-type estrogen receptor beta (ERbeta1). However, it is still unclear whether the ERbeta expression is related to EMT, invasion and metastasis in breast cancer. In the present study, we examined whether ERbeta1 through regulating EMT can influence invasion and metastasis in basal-like cancers.Basal-like breast cancer cells (MDA-MB-231 and Hs578T) in which ERbeta1 was either overexpressed or downregulated were analyzed for their ability to migrate and invade (wound-healing assay, matrigel-coated Transwell assay) as well as for the expression of EMT markers and components of the EGFR pathway (immunoblotting, RT-PCR). Coimmunoprecipitation and ubiquitylation assays were employed to examine whether ERbeta1 alters EGFR protein degradation and the interaction between EGFR and the ubiquitin ligase c-Cbl. The metastatic potential of the ERbeta1-expressing MDA-MB-231 cells was evaluated in vivo in a zebrafish xenotransplantation model and the correlation between ERbeta1 and E-cadherin expression was examined in 208 clinical breast cancer specimens by immunohistochemistry.Here we show that ERbeta1 inhibits EMT and invasion in basal-like breast cancer cells when they grow either in vitro or in vivo in zebrafish. The inhibition of EMT correlates with an ERbeta1-mediated upregulation of miR-200a/b/429 and the subsequent repression of ZEB1 and SIP1, which results in increased expression of E-cadherin. The positive correlation of ERbeta1 and E-cadherin expression was additionally observed in breast tumor samples. Downregulation of the basal marker EGFR through stabilization of the ubiquitin ligase c-Cbl complexes and subsequent ubiquitylation and degradation of the activated receptor is involved in the ERbeta1-mediated repression of EMT and induction of EGFR signaling abolished the ability of ERbeta1 to sustain the epithelial phenotype.Taken together, the results of our study strengthen the association of ERbeta1 with the regulation of EMT and propose the receptor as a potential crucial marker in predicting metastasis in breast cancer.

Dataset Information

Phytosphingosine exhibits an anti-epithelial-mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells.

Publications

Phytosphingosine exhibits an anti-epithelial-mesenchymal transition function by the inhibition of EGFR signaling in human breast cancer cells.

Similar Datasets

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