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Wnt signaling in triple negative breast cancer is associated with metastasis.
Wnt signaling in triple negative breast cancer is associated with metastasis.
- Source :
-
BMC cancer [BMC Cancer] 2013 Nov 10; Vol. 13, pp. 537. Date of Electronic Publication: 2013 Nov 10. - Publication Year :
- 2013
-
Abstract
- Background: Triple Negative subset of (TN) Breast Cancers (BC), a close associate of the basal-like subtype (with limited discordance) is an aggressive form of the disease which convey unpredictable, and poor prognosis due to limited treatment options and lack of proven effective targeted therapies.<br />Methods: We conducted an expression study of 240 formalin-fixed, paraffin-embedded (FFPE) primary biopsies from two cohorts, including 130 TN tumors, to identify molecular mechanisms of TN disease.<br />Results: The annotation of differentially expressed genes in TN tumors contained an overrepresentation of canonical Wnt signaling components in our cohort and others. These observations were supported by upregulation of experimentally induced oncogenic Wnt/β-catenin genes in TN tumors, recapitulated using targets induced by Wnt3A. A functional blockade of Wnt/β-catenin pathway by either a pharmacological Wnt-antagonist, WntC59, sulidac sulfide, or β-catenin (functional read out of Wnt/β-catenin pathway) SiRNA mediated genetic manipulation demonstrated that a functional perturbation of the pathway is causal to the metastasis- associated phenotypes including fibronectin-directed migration, F-actin organization, and invasion in TNBC cells. A classifier, trained on microarray data from β-catenin transfected mammary cells, identified a disproportionate number of TNBC breast tumors as compared to other breast cancer subtypes in a meta-analysis of 11 studies and 1,878 breast cancer patients, including the two cohorts published here. Patients identified by the Wnt/β-catenin classifier had a greater risk of lung and brain, but not bone metastases.<br />Conclusion: These data implicate transcriptional Wnt signaling as a hallmark of TNBC disease associated with specific metastatic pathways.
- Subjects :
- Biomarkers, Tumor metabolism
Blotting, Western
Bone Neoplasms genetics
Bone Neoplasms metabolism
Brain Neoplasms genetics
Brain Neoplasms metabolism
Cell Movement
Cell Proliferation
Cohort Studies
Female
Follow-Up Studies
Gene Expression Profiling
Gene Expression Regulation, Neoplastic
Humans
Immunoenzyme Techniques
Lung Neoplasms genetics
Lung Neoplasms metabolism
Neoplasm Recurrence, Local genetics
Neoplasm Recurrence, Local metabolism
Neoplasm Recurrence, Local pathology
Neoplasm Staging
Oligonucleotide Array Sequence Analysis
Paraffin Embedding
Prognosis
RNA, Messenger genetics
RNA, Small Interfering genetics
Real-Time Polymerase Chain Reaction
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Survival Rate
Triple Negative Breast Neoplasms genetics
Triple Negative Breast Neoplasms metabolism
Tumor Cells, Cultured
Wnt Proteins genetics
beta Catenin antagonists & inhibitors
beta Catenin genetics
Biomarkers, Tumor genetics
Bone Neoplasms secondary
Brain Neoplasms secondary
Lung Neoplasms secondary
Triple Negative Breast Neoplasms pathology
Wnt Proteins metabolism
beta Catenin metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1471-2407
- Volume :
- 13
- Database :
- MEDLINE
- Journal :
- BMC cancer
- Publication Type :
- Academic Journal
- Accession number :
- 24209998
- Full Text :
- https://doi.org/10.1186/1471-2407-13-537