title: TGF-beta receptor type-2 expression in cancer-associated fibroblasts regulates breast cancer cell growth and survival and is a prognostic marker in pre-menopausal breast cancer.
abstract: Transforming growth factor-beta (TGF-β) is a pleiotropic cytokine with the capability to act as tumour suppressor or tumour promoter depending on the cellular context. TGF-beta receptor type-2 (TGFBR2) is the ligand-binding receptor for all members of the TGF-β family. Data from mouse model experiments demonstrated that loss of Tgfbr2 expression in mammary fibroblasts was linked to tumour initiation and metastasis. Using a randomised tamoxifen trial cohort including in total 564 invasive breast carcinomas, we examined TGFBR2 expression (n=252) and phosphorylation level of downstream target SMAD2 (pSMAD2) (n=319) in cancer-associated fibroblasts (CAFs) and assessed links to clinicopathological markers, prognostic and treatment-predictive values. The study revealed that CAF-specific TGFBR2 expression correlated with improved recurrence-free survival. Multivariate analysis confirmed CAF-TGFBR2 to be an independent prognostic marker (multivariate Cox regression, hazard ratio: 0.534, 95% (CI): 0.360-0.793, P=0.002). CAF-specific pSMAD2 levels, however, did not associate with survival outcome. Experimentally, TGF-β signalling in fibroblasts was modulated using a TGF-β ligand and inhibitor or through lentiviral short hairpin RNA-mediated TGFBR2-specific knockdown. To determine the role of fibroblastic TGF-β pathway on breast cancer cells, we used cell contact-dependent cell growth and clonogenicity assays, which showed that knockdown of TGFBR2 in CAFs resulted in increased cell growth, proliferation and clonogenic survival. Further, in a mouse model transfected CAFs were co-injected with MCF7 and tumour weight and proportion was monitored. We found that mouse xenograft tumours comprising TGFBR2 knockdown fibroblasts were slightly bigger and displayed increased tumour cell capacity. Overall, our data demonstrate that fibroblast-related biomarkers possess clinically relevant information and that fibroblasts confer effects on breast cancer cell growth and survival. Regulation of tumour-stromal cross-talk through fibroblastic TGF-β pathway may depend on fibroblast phenotype, emphasising the importance to characterise tumour microenvironment subtypes.
authors: Department of Pathology, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
authors: S
authors: S
authors: Busch
authors: Wellcome Trust Centre for Cell Matrix Research, Faculty of Life Sciences, University of Manchester, Michael Smith Building, Manchester, UK.
authors: A
authors: A
authors: Acar
authors: Department of Pathology, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
authors: Y
authors: Y
authors: Magnusson
authors: Department of Pathology, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden.
authors: P
authors: P
authors: Gregersson
authors: Department of Surgery, Institution of Clinical Sciences, Lund University Hospital, Lund, Sweden.
authors: L
authors: L
authors: Rydén
authors: 1] Department of Pathology, Sahlgrenska Cancer Center, Gothenburg University, Gothenburg, Sweden [2] Molecular Pathology Group, Breakthrough Breast Cancer Research Unit, Institute of Cancer Sciences, University of Manchester, Paterson Institute for Cancer Research, Manchester, UK.
authors: G
authors: G
authors: Landberg
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor; D001943:Breast Neoplasms / Q000378:metabolism*; D002454:Cell Differentiation; D049109:Cell Proliferation; D002470:Cell Survival; D018572:Disease-Free Survival; D005260:Female; D005347:Fibroblasts / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D010766:Phosphorylation; D011237:Predictive Value of Tests; D017697:Premenopause; D011379:Prognosis; D016016:Proportional Hazards Models; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism*; D015398:Signal Transduction; D013629:Tamoxifen / Q000627:therapeutic use; D016212:Transforming Growth Factor beta / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D018125:Receptors, Transforming Growth Factor beta; C508960:TGFB1 protein, human; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D013629:Tamoxifen; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II