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WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling.

ABSTRACT: BACKGROUND:Breast cancer is the leading cause of cancer-related death in women worldwide. Metastatic disease remains the primary cause of death in patients with breast cancer. Basal-like breast cancer (BLBC) is associated with aggressive behavior, stem-like phenotype, high histological grade, poor clinical features, and high rates of recurrences and/or metastasis. However, the mechanism of BLBC phenotype shaping remains obscure. METHODS:Seventeen normal breast/breast cancer cell lines were used for evaluating the breast cancer subtype-markers, WNT targets and constitutive components, and epithelial mesenchymal transition (EMT) markers analysis by western blot. One hundred and twenty formalin-fixed breast cancer tissues were used for immunohistochemistry (IHC) staining. Nine online platforms (cBioPortal, CCLE, GEPIA, etc.) were used for related analyses. RESULTS:We identified Wnt5b as a key regulatory factor that governs the phenotype of BLBC by activating canonical and non-canonical WNT signaling. Wnt5b exhibited basal-like specificity in cells and clinical samples both at the mRNA and protein levels and also showed good correlation with basal-like phenotype at the mRNA level. Besides, Wnt5b was also a promising therapeutic target for LGK-974 treatment. In addition, we identified that CK1? was expressed at low levels in BLBC and that the activation of CK1? by pyrvinium was an alternative strategy for BLBC treatment. CONCLUSIONS:Wnt5b is not only a diagnostic biomarker but also a potential therapeutic target of BLBC.

SUBMITTER: Jiang S

PROVIDER: S-EPMC6714433 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling.

Jiang Shaojie S Zhang Miaofeng M Zhang Yanhua Y Zhou Weiping W Zhu Tao T Ruan Qing Q Chen Hui H Fang Jie J Zhou Fei F Sun Jihong J Yang Xiaoming X

Cell communication and signaling : CCS 20190828 1

<h4>Background</h4>Breast cancer is the leading cause of cancer-related death in women worldwide. Metastatic disease remains the primary cause of death in patients with breast cancer. Basal-like breast cancer (BLBC) is associated with aggressive behavior, stem-like phenotype, high histological grade, poor clinical features, and high rates of recurrences and/or metastasis. However, the mechanism of BLBC phenotype shaping remains obscure.<h4>Methods</h4>Seventeen normal breast/breast cancer cell l ...[more]

PMID: 31462314

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Project description:Purpose:Evidence describing TMED3 in the context of breast cancer is scarce, and the effect of TMED3 on Wnt/?-catenin signaling in breast cancer has not been reported. The objective of this study was to determine the potential physiological functions and molecular mechanisms of TMED3 in breast cancer. Materials and Methods:Quantitative real-time PCR and Western blot analysis were used to analyze the expression of TMED3 mRNA and protein in 182 paraffin-embedded primary breast cancer tissues and 60 paired noncancerous tissues and 25 fresh primary breast cancer tissues and surrounding adjacent noncancerous tissues. Associations between TMED3 expression and clinicopathologic factors or overall survival were determined. The effects of overexpression or knockdown of TMED3 on proliferation, migration, invasion, and cell cycle progression in breast cancer cell lines were investigated with the Cell Counting Kit-8, clone formation assay, transwell assay, wound healing assay, and flow cytometry, respectively. Immunofluorescence and Western blot analysis were used to detect the expression of cell cycle, migration-related, and Wnt/?-catenin signaling proteins. Results:The expression of TMED3 mRNA and protein were significantly increased in breast cancer tissues and cell lines compared to normal controls. TMED3 upregulation was significantly correlated with clinicopathologic characteristics and predicted poor prognosis in patients with breast cancer. TMED3 overexpression promoted proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 knockdown suppressed proliferation, migration, invasion, and cell cycle progression compared to controls in breast cancer cell lines. TMED3 promoted proliferation and migration of breast cancer cells by a mechanism that involved Wnt/?-catenin signaling. Conclusion:TMED3 behaves as an oncogene that promotes the proliferation and migration of breast cancer cells by a mechanism that involved Wnt/?-catenin signaling. Strategies targeting TMED3 have potential therapeutic implications for patients with breast cancer.

Project description:Breast cancer is a heterogeneous disease that comprises multiple subtypes. Luminal subtype tumors confer a more favorable patient prognosis, which is, in part, attributed to estrogen receptor (ER)-? positivity and antihormone responsiveness. Expression of the forkhead box transcription factor, FOXA1, similarly correlates with the luminal subtype and patient survival, but is also present in a subset of ER-negative tumors. FOXA1 is also consistently expressed in luminal breast cancer cell lines even in the absence of ER. In contrast, breast cancer cell lines representing the basal subtype do not express FOXA1. To delineate an ER-independent role for FOXA1 in maintaining the luminal phenotype, and hence a more favorable prognosis, we performed expression microarray analyses on FOXA1-positive and ER-positive (MCF7, T47D), or FOXA1-positive and ER-negative (MDA-MB-453, SKBR3) luminal cell lines in the presence or absence of transient FOXA1 silencing. This resulted in three FOXA1 transcriptomes: (1) a luminal signature (consistent across cell lines), (2) an ER-positive signature (restricted to MCF7 and T47D) and (3) an ER-negative signature (restricted to MDA-MB-453 and SKBR3). Gene set enrichment analyses revealed FOXA1 silencing causes a partial transcriptome shift from luminal to basal gene expression signatures. FOXA1 binds to a subset of both luminal and basal genes within luminal breast cancer cells, and loss of FOXA1 increases enhancer RNA transcription for a representative basal gene (CD58). These data suggest FOXA1 directly represses a subset of basal signature genes. Functionally, FOXA1 silencing increases migration and invasion of luminal cancer cells, both of which are characteristics of basal subtype cells. We conclude FOXA1 controls plasticity between basal and luminal breast cancer cells, not only by inducing luminal genes but also by repressing the basal phenotype, and thus aggressiveness. Although it has been proposed that FOXA1-targeting agents may be useful for treating luminal tumors, these data suggest that this approach may promote transitions toward more aggressive cancers.

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WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling.

Publications

WNT5B governs the phenotype of basal-like breast cancer by activating WNT signaling.

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