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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.

Busch, S; Acar, A; Magnusson, Y; Gregersson, P; Rydén, Lisa LU and Landberg, G (2015) In Oncogene 34(1). p.27-38
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... (More)
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.Oncogene advance online publication, 16 December 2013; doi:10.1038/onc.2013.527. (Less)
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type
Contribution to journal
publication status
published
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in
Oncogene
volume
34
issue
1
pages
27 - 38
publisher
Nature Publishing Group
external identifiers
  • wos:000349740100003
  • pmid:24336330
  • scopus:84925287388
ISSN
1476-5594
DOI
10.1038/onc.2013.527
language
English
LU publication?
yes
id
320f7f99-69a9-4f15-8915-ac9062af4022 (old id 4223697)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/24336330?dopt=Abstract
date added to LUP
2014-01-04 18:11:01
date last changed
2017-10-29 03:05:11
@article{320f7f99-69a9-4f15-8915-ac9062af4022,
  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.Oncogene advance online publication, 16 December 2013; doi:10.1038/onc.2013.527.},
  author       = {Busch, S and Acar, A and Magnusson, Y and Gregersson, P and Rydén, Lisa and Landberg, G},
  issn         = {1476-5594},
  language     = {eng},
  number       = {1},
  pages        = {27--38},
  publisher    = {Nature Publishing Group},
  series       = {Oncogene},
  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.},
  url          = {http://dx.doi.org/10.1038/onc.2013.527},
  volume       = {34},
  year         = {2015},
}