Wnt modulates MCL1 to control cell survival in triple negative breast cancer

Lixin Yang, Aldwin A. Perez, Sayuri Fujie, Charles Warden, Jie Li, Yafan Wang, Bryan Yung, Yun Ru Chen, Xiyong Liu, Hang Zhang, Shu Zheng, Zheng Liu, David Ann, Yun Yen

Research output: Contribution to journalArticle

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Abstract

Background: Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells.Methods: We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test.Results: WNT5B was elevated both in the tumor and the patients' serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with enhanced metastasis and decreased disease-free survival.Conclusions: All our findings suggested that WNT5B/MCL1 cascade is critical for TNBC and understanding its regulatory apparatus provided valuable insight into the pathogenesis of the tumor development and the guidance for targeting therapeutics.

Original languageEnglish
Article number124
JournalBMC Cancer
Volume14
Issue number1
DOIs
Publication statusPublished - Feb 24 2014
Externally publishedYes

Fingerprint

Triple Negative Breast Neoplasms
Cell Survival
Microarray Analysis
Ligands
Immunohistochemistry
Apoptosis
Staining and Labeling
Neoplasm Metastasis
G1 Phase Cell Cycle Checkpoints
Catenins
Oxidative Phosphorylation
Organelle Biogenesis
Caspases
Mitochondrial DNA
Oxygen Consumption
Wound Healing
Disease-Free Survival
Cell Movement
Neoplasms
Cell Cycle

Keywords

  • MCL1
  • Triple negative breast cancer (TNBC)
  • WNT/β-catenin pathway
  • WNT5B

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Wnt modulates MCL1 to control cell survival in triple negative breast cancer. / Yang, Lixin; Perez, Aldwin A.; Fujie, Sayuri; Warden, Charles; Li, Jie; Wang, Yafan; Yung, Bryan; Chen, Yun Ru; Liu, Xiyong; Zhang, Hang; Zheng, Shu; Liu, Zheng; Ann, David; Yen, Yun.

In: BMC Cancer, Vol. 14, No. 1, 124, 24.02.2014.

Research output: Contribution to journalArticle

Yang, L, Perez, AA, Fujie, S, Warden, C, Li, J, Wang, Y, Yung, B, Chen, YR, Liu, X, Zhang, H, Zheng, S, Liu, Z, Ann, D & Yen, Y 2014, 'Wnt modulates MCL1 to control cell survival in triple negative breast cancer', BMC Cancer, vol. 14, no. 1, 124. https://doi.org/10.1186/1471-2407-14-124
Yang L, Perez AA, Fujie S, Warden C, Li J, Wang Y et al. Wnt modulates MCL1 to control cell survival in triple negative breast cancer. BMC Cancer. 2014 Feb 24;14(1). 124. https://doi.org/10.1186/1471-2407-14-124
Yang, Lixin ; Perez, Aldwin A. ; Fujie, Sayuri ; Warden, Charles ; Li, Jie ; Wang, Yafan ; Yung, Bryan ; Chen, Yun Ru ; Liu, Xiyong ; Zhang, Hang ; Zheng, Shu ; Liu, Zheng ; Ann, David ; Yen, Yun. / Wnt modulates MCL1 to control cell survival in triple negative breast cancer. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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AU - Perez, Aldwin A.

AU - Fujie, Sayuri

AU - Warden, Charles

AU - Li, Jie

AU - Wang, Yafan

AU - Yung, Bryan

AU - Chen, Yun Ru

AU - Liu, Xiyong

AU - Zhang, Hang

AU - Zheng, Shu

AU - Liu, Zheng

AU - Ann, David

AU - Yen, Yun

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N2 - Background: Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells.Methods: We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test.Results: WNT5B was elevated both in the tumor and the patients' serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with enhanced metastasis and decreased disease-free survival.Conclusions: All our findings suggested that WNT5B/MCL1 cascade is critical for TNBC and understanding its regulatory apparatus provided valuable insight into the pathogenesis of the tumor development and the guidance for targeting therapeutics.

AB - Background: Triple negative breast cancer (TNBC) has higher rates of recurrence and distant metastasis, and poorer outcome as compared to non-TNBC. Aberrant activation of WNT signaling has been detected in TNBC, which might be important for triggering oncogenic conversion of breast epithelial cell. Therefore, we directed our focus on identifying the WNT ligand and its underlying mechanism in TNBC cells.Methods: We performed large-scale analysis of public microarray data to screen the WNT ligands and the clinical significance of the responsible ligand in TNBC. WNT5B was identified and its overexpression in TNBC was confirmed by immunohistochemistry staining, Western blot and ELISA. ShRNA was used to knockdown WNT5B expression (shWNT5B). Cellular functional alteration with shWNT5B treatment was determined by using wound healing assay, mammosphere assay; while cell cycle and apoptosis were examined by flowcytometry. Mitochondrial morphology was photographed by electron microscope. Biological change of mitochondria was detected by RT-PCR and oxygen consumption assay. Activation of WNT pathway and its downstream targets were evaluated by liciferase assay, immunohistochemistry staining and immunoblot analysis. Statistical methods used in the experiments besides microarray analysis was two-tailed t-test.Results: WNT5B was elevated both in the tumor and the patients' serum. Suppression of WNT5B remarkably impaired cell growth, migration and mammosphere formation. Additionally, G0/G1 cell cycle arrest and caspase-independent apoptosis was observed. Study of the possible mechanism indicated that these effects occurred through suppression of mitochondrial biogenesis, as evidenced by reduced mitochondrial DNA (MtDNA) and compromised oxidative phosphorylation (OXPHOS). In Vivo and in vitro data uncovered that WNT5B modulated mitochondrial physiology was mediated by MCL1, which was regulated by WNT/β-catenin responsive gene, Myc. Clinic data analysis revealed that both WNT5B and MCL1 are associated with enhanced metastasis and decreased disease-free survival.Conclusions: All our findings suggested that WNT5B/MCL1 cascade is critical for TNBC and understanding its regulatory apparatus provided valuable insight into the pathogenesis of the tumor development and the guidance for targeting therapeutics.

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