Journal
CANCER RESEARCH
Volume 79, Issue 10, Pages 2619-2633Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-18-2787
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Funding
- Irish Cancer Society Collaborative Cancer Centre Breast Predict [CCRC13GAL]
- Science Foundation Ireland [11/PI/1139, 16/IA/4505]
- European Union [251480, 258967]
- HSC Research and Development Division of the Public Health Agency in Northern Ireland
- Cancer Research UK through the Belfast CR-UK Centre
- Northern Ireland Experimental CancerMedicine Centre
- Friends of the Cancer Centre
- Cancer Research UK
- Sean Crummey Foundation
- Science Foundation Ireland (SFI) [16/IA/4505, 11/PI/1139] Funding Source: Science Foundation Ireland (SFI)
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The PDLIM2 protein regulates stability of transcription factors including NF-kappa B and STATs in epithelial and hemopoietic cells. PDLIM2 is strongly expressed in certain cancer cell lines that exhibit an epithelial-to-mesenchymal phenotype, and its suppression is sufficient to reverse this phenotype. PDLIM2 supports the epithelial polarity of non-transformed breast cells, suggesting distinct roles in tumor suppression and oncogenesis. To better understand its overall function, we investigated PDLIM2 expression and activity in breast cancer. PDLIM2 protein was present in 60% of tumors diagnosed as triple-negative breast cancer (TNBC), and only 20% of other breast cancer subtypes. High PDLIM2 expression in TNBC was positively correlated with adhesion signaling and beta-catenin activity. Interestingly, PDLIM2 was restricted to the cytoplasm/membrane of TNBC cells and excluded from the nucleus. In breast cell lines, PDLIM2 retention in the cytoplasm was controlled by cell adhesion, and translocation to the nucleus was stimulated by insulin-like growth factor-1 or TGF beta. Cytoplasmic PDLIM2 was associated with active beta-catenin and ectopic expression of PDLIM2 was sufficient to increase beta-catenin levels and its transcriptional activity in reporter assays. Suppression of PDLIM2 inhibited tumor growth in vivo, whereas overexpression of PDLIM2 disrupted growth in 3D cultures. These results suggest that PDLIM2 may serve as a predictive biomarker for a large subset of TNBC whose phenotype depends on adhesion-regulated beta-catenin activity and which may be amenable to therapies that target these pathways. Significance: This study shows that PDLIM2 expression defines a subset of triple-negative breast cancer that may benefit from targeting the beta-catenin and adhesion signaling pathways.
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