TGF-beta1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival.
Transforming growth factor-beta (TGF-beta)-mediated signals play complicated roles in the development and progression of breast tumour. The purposes of this study were to analyse the genotype of TGF-beta1 at T29C and TGF-beta1 phenotype in breast tumours, and to evaluate their associations with IGFs and clinical characteristics of breast cancer. Fresh tumour samples were collected from 348 breast cancer patients. TGF-beta1 genotype and phenotype were analysed with TaqMan and ELISA, respectively. Members of the IGF family in tumour tissue were measured with ELISA. Cox proportional hazards regression analysis was performed to assess the association of TGF-beta1 and disease outcomes. Patients with the T/T (29%) genotype at T29C had the highest TGF-beta1, 707.9 pg mg(-1), followed by the T/C (49%), 657.8 pg mg(-1), and C/C (22%) genotypes, 640.8 pg mg(-1), (P=0.210, T/T vs C/C and C/T). TGF-beta1 concentrations were positively correlated with levels of oestrogen receptor, IGF-I, IGF-II and IGFBP-3. Survival analysis showed TGF-beta1 associated with disease progression, but the association differed by disease stage. For early-stage disease, patients with the T/T genotype or high TGF-beta1 had shorter overall survival compared to those without T/T or with low TGF-beta1; the hazard ratios (HR) were 3.54 (95% CI: 1.21-10.40) for genotype and 2.54 (95% CI: 1.10-5.89) for phenotype after adjusting for age, grade, histotype and receptor status. For late-stage disease, however, the association was different. The T/T genotype was associated with lower risk of disease recurrence (HR=0.13, 95% CI: 0.02-1.00), whereas no association was found between TGF-beta1 phenotype and survival outcomes. The study suggests a complex role of TGF-beta1 in breast cancer progression, which supports the finding of in vitro studies that TGF-beta1 has conflicting effects on tumour growth and metastasis.
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Department of Epidemiology and Public Health, Yale Cancer Center, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
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D000368:Aged; D001943:Breast Neoplasms / Q000235:genetics* / Q000401:mortality*; D018450:Disease Progression; D018572:Disease-Free Survival; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005838:Genotype; D006801:Humans; D008875:Middle Aged; D010641:Phenotype; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide; D011960:Receptors, Estrogen / Q000378:metabolism; D013002:Somatomedins / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000235:genetics*
D011960:Receptors, Estrogen; D013002:Somatomedins; D053773:Transforming Growth Factor beta1