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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 . 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 .
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Outcome_Other
P=0.002 ) .
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Outcome_Physical
CAF-specific pSMAD2 levels
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Outcome_Physical
TGF-β signalling in fibroblasts
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Outcome_Physical
cell growth
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Outcome_Physical
proliferation
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Outcome_Physical
clonogenic survival
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Outcome_Physical
MCF7 and tumour weight and proportion
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Participant_Condition
from mouse model experiments
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Participant_Condition
Using a randomised tamoxifen trial cohort
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Participant_Sample-size
564
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Participant_Condition
breast carcinomas
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Participant_Condition
in a mouse model