Transforming growth factor‑β, insulin‑like growth factor I/insulin‑like growth factor I receptor and vascular endothelial growth factor‑A: Prognostic and predictive markers in triple‑negative and non‑triple‑negative breast cancer (original) (raw)
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The prognostic values of insulin-like growth factor binding protein in breast cancer
Medicine, 2019
Insulin-like growth factor binding proteins (IGFBPs) are a family of proteins binding to insulin-like growth factors, generally consisting 6 high-affinity IGFBPs, namely IGFBP1 through IGFBP6. IGFBP family members have been indicated to be involved in the development and progression of tumors and may be useful prognostic biomarkers in various malignancies. However, the prognostic role of individual IGFBPs, especially at the mRNA level in breast cancer patients remains elusive. We accessed the prognostic roles of IGFBPs family (IGFBP1-6) in breast cancer through the "Kaplan-Meier plotter" online database and OncoLnc database. Our results showed that the high expression of IGFBP1 mRNA was associated with favorable relapsed free survival (RFS) in all breast cancer patients. The high expression of IGFBP2 mRNA was associated with favorable overall survival (OS) and RFS in all breast cancer patients. The high expression of IGFBP3 mRNA was significantly correlated to worsen RFS in all breast cancer patients. The high expression of IGFBP4 mRNA was associated with favorable OS, RFS, distant metastasis-free survival, and postprogression survival in all breast cancer patients. Our results indicated that expression of IGFBPs mRNA may have prognostic values in breast cancer patients, and have a benefit for developing tools to predict the prognosis more accurately. Abbreviations: CI = confidence intervals, DMFS = distant metastasis-free survival, ER = estrogen receptor, HR = hazard ratio, IGFBP = insulin-like growth factor binding proteins, IGFs = insulin-like growth factors, KM plotter = Kaplan-Meier plotter, OS = overall survival, PAPP-A = pregnancy-associated plasma protein-A, PPS = post-progression survival, RFS = favorable relapsed free survival.
cant independent prognostic value. Because IGF-I and Insulinlike growth factor I (IGF-I) is a single-polypep-IGFBP-3 were closely correlated, they contained almost tide chain with important anabolic and endocrine activithe same prognostic information. Inclusion of IGF-I gave ties. The liver is the major source of IGF-I and its binding these results: IGF-I (P õ .03), alcohol intake (P õ .02), protein, IGFBP-3. Circulating concentrations of IGF-I coagulation factors 2, 7, and 10 (P õ .01), creatinine (P and IGFBP-3 are decreased in patients with chronic õ .001), and IgM (P õ .01) contained independent progliver disease and correlate with the severity. The aim of nostic information. Inclusion of IGFBP-3 gave these rethis study was to assess the additional prognostic value sults: IGFBP-3 (P õ .02), alcohol intake (P õ .05), coagulaof IGF-I and IGFBP-3 in patients entered in a large tion factors 2, 7, 10 (P õ .01), creatinine (P õ .001), and multicenter study (EMALD). Three hundred thirty-IgM (P õ .02) were independent predictors of survival. seven patients with alcohol-induced liver disease were
Insulin-like growth factor receptor (IGF-1R) in breast cancer subtypes
Breast Cancer Research and Treatment, 2012
Insulin-like growth factor-1 receptor (IGF-1R) is expressed in normal and malignant breast tissue and has been implicated in cell survival and resistance to cytotoxic therapies. We sought to assess the prognostic impact of IGF-1R expression among patients with early breast cancer and among breast cancer subtypes. Patients with stages I-III breast cancer with archival tumor tissue were included. Paraffin tissue blocks were used to construct a tissue microarray that was stained for ER, PR, Ki-67, HER2, EGFR, and cytokeratins 5/6 to classify the breast subgroups and for expression of IGF-1R, p27, and Bcl2 by immunohistochemistry. Kaplan-Meier plots were created by subtypes. Associations between IGF-1R and prognostic variables were examined in multivariate analysis. Among 2,871 eligible women the prognostic cut point for IGF-1R expression for breast-cancer-specific survival (BCSS) was Allred score \7 versus C7. IGF-1R was C7 in 52% (LuminalA), 57.5% (LuminalB), 44.8% (LuminalHER2), 9.7% HER2-enriched, and 22.5% (Basal-like), P = 1.3 9 10 -52 . IGF-1R? was associated with age C50, lower histopathology grade, ER?, HER2 negativity (-), high p27 and high Bcl2 score. IGF-1R C7 was associated with better BCSS among LuminalB patients, hazard ratio = 0.64 (0.49-0.84); P = 1.2 9 10 -3, and worse outcome in the HER2-enriched subtype, hazard ratio = 2.37 (1.21-4.64); P = 0.012. IGF-1R correlates with good prognostic markers among patients with early breast cancer and is differentially expressed with variable prognostic impact among breast cancer subtypes. Results may have relevance to the development of therapeutics targeting IGF-1R.
International Journal of Cancer, 2013
Elevated circulating insulin-like growth factor-1 (IGF-1), a breast epithelial cell mitogen, is associated with breast cancer development. However, its association with breast cancer survival is not established. Circulating concentrations of IGF-1 are controlled via binding proteins, including IGF Binding Protein-3 (IGFBP-3), that may modulate the association of IGF-1 with breast-cancer outcomes. We measured IGF-1 and IGFBP-3 concentrations in serum from 600 women enrolled in the health, eating, activity, and lifestyle (HEAL) study, a multiethnic, prospective cohort study of women diagnosed with stage I-IIIA breast cancer. We evaluated the association between IGF-1 and IGFBP-3, and as a ratio, modeled using quintile cut-points, with risk of breast cancer-specific (n 5 42 deaths) and all-cause mortality (n 5 87 deaths) using Cox proportional hazards models. In models adjusted for body mass index, ethnicity, tamoxifen use at time of blood draw, treatment received at diagnosis and IGFBP-3, women in the highest quintile of IGF-1 level had an increased risk of all-cause mortality (Hazard Ratio (HR) 5 3.10, 95% CI 1.21-7.93, p 5 0.02), although no dose-response association was evident. The IGF-1/IGFBP-3 ratio, an indicator of free IGF-I levels, was significantly associated with increasing risk of all-cause mortality (HR 5 2.83, 95% CI 1.25-6.36 p trend 5 0.01, upper vs. lower quintile) in a fully adjusted model. In conclusion, high serum levels of IGF-1 and the IGF-1/IGFBP-3 ratio were associated with increased risk of all-cause mortality in women with breast cancer. These results need to be confirmed in larger breast cancer survivor cohorts.
The prognostic significance of transforming growth factors in human breast cancer
British journal of cancer, 1993
Transforming growth factor alpha (TGF alpha) and Transforming growth factor beta-1 (TGF-beta 1) are growth regulatory for breast cancer cell lines in vitro and several studies have suggested that levels of the receptor for TGF alpha, the epidermal growth factor (EGFR) in tumour biopsies predict relapse and survival. We have examined the prognostic significance of TGF alpha, TGF-beta 1 and EGFR mRNA expression in a series of patients with primary breast cancer with a median follow up period of 60 months. In 167 patients the expression of TGF-beta 1 was inversely correlated with node status (P = 0.065) but not ER status, tumour size or menopausal status. Patients with high levels of TGF-beta 1 had a longer disease free interval with a significantly longer probability of survival at 80 months although the overall relapse free survival was not increased. EGFR mRNA expression was measured in 106 patients and was inversely correlated with ER status (P = 0.018). EGFR levels did not predict...
European Journal of Cancer, 2003
We examined the association between an elevated plasma TGF-b 1 level and the disease progression of advanced breast cancer (BC) patients (n=44). TGF-b 1 levels were detected by an enzyme-linked immunosorbent assay (ELISA). Platelet carryover and in vitro platelet activation in our plasma samples was assessed and found to be insignificant. Plasma TGF-b 1 values were significantly elevated (P <0.05) in stage IIIB/IV patients (median value: 2.40 ng/ml, range: 0.13-8.48 ng/ml, n=44) compared with healthy donors (median value: 1.30 ng/ml, range: 0.41-4.93 ng/ml, n=36). Although pronounced in metastatic patients, especially those who had been newly diagnosed, TGF-b 1 elevation was independent of tumour mass, site of distant metastases, histopathological type, steroid receptor (SR) content and age of the BC patients. Follow-up of 6 patients indicated a relationship between the plasma TGF-b 1 and the patient's response. This suggests that TGF-b 1 , may be a promising prognostic marker for breast cancer patients with advanced disease. Confirmatory large-scale studies are needed, particularly given the overlap of values between our different subgroups analysed. #
Insulin-like growth factor–binding protein-3 and breast cancer survival
International Journal of Cancer, 1998
Insulin-like growth factors (IGFs) interact with specific cell surface receptors to mediate cell growth. Intracellular effects of the IGFs are mediated by activation of secondary messenger molecules. One of these proteins, insulin receptor substrate-l (IRS-i), is phosphorylated after type I IGF receptor activation and has a major role in IGF signaling. Receptor activation also is influenced by high-affinity IGF binding proteins (IGFBPs). In serum, IGFBP-3 is the pre. dominant species. The role of IGFBP-3 in the regulation of breast cancer cell growth is unclear; both growth inhibition and stimulation have been documented in tissue culture systems. To investigate the influence of IGFBP-3 and IRS-i in breast cancer, we measured levels of these proteins by ELISA and immunoblotting in i95 node-negative primary human breast cancers and compared their levels with known prognostic factors and disease-free survival (DFS). IGFBP-3 levels correlated positively with tumor size (r 0.27, P < 0.0001) and negatively with estrogen receptor (r -0.35, P < 0.000i) and progesterone receptor (r = -0.16, P = 0.021). In contrast, IRS-i did not correlate with prognostic factors, but higher levels of IRS-i predicted worse DFS for the subset of patients with tumors 2 cm (P 0.04), and for patients with estrogen receptor-positive tumors, there was a trend toward worse DFS (P 0.06). These results suggest that higher tumor levels of IGFBP-3 are associated with worse features in breast cancer. However, IGFBP-3 was not an independent prognostic
TGF-β1 genotype and phenotype in breast cancer and their associations with IGFs and patient survival
British Journal of Cancer, 2008
Transforming growth factor-b (TGF-b)-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-b1 at T29C and TGF-b1 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-b1 genotype and phenotype were analysed with TaqMan s 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-b1 and disease outcomes. Patients with the T/T (29%) genotype at T29C had the highest TGF-b1, 707.9 pg mg À1 , followed by the T/C (49%), 657.8 pg mg À1 , and C/C (22%) genotypes, 640.8 pg mg À1 , (P ¼ 0.210, T/T vs C/C and C/T). TGF-b1 concentrations were positively correlated with levels of oestrogen receptor, IGF-I, IGF-II and IGFBP-3. Survival analysis showed TGF-b1 associated with disease progression, but the association differed by disease stage. For early-stage disease, patients with the T/T genotype or high TGF-b1 had shorter overall survival compared to those without T/T or with low TGF-b1; 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 ¼ 0.13, 95% CI: 0.02 -1.00), whereas no association was found between TGF-b1 phenotype and survival outcomes. The study suggests a complex role of TGF-b1 in breast cancer progression, which supports the finding of in vitro studies that TGF-b1 has conflicting effects on tumour growth and metastasis.
PLoS ONE, 2014
Introduction: We sought to determine the level of protein expression of the critical components of the insulin-like growth factor receptor (IGFR) pathway and to evaluate their prognostic significance across the different early breast cancer subtypes. Patients and Methods: Archival tumor tissue from 1,021 women with early, node positive breast cancer, who were prospectively evaluated within two randomized clinical trials, was used to construct tissue microarrays that were stained for hormone receptors (HR), Ki67, HER2, epidermal growth factor receptor (EGFR) and cytokeratins 5/6, to classify tumors into five immunophenotypical subgroups. Immunohistochemical (IHC) expression of IGF1R-alpha and beta subunits, IGF2R and IGF-binding protein 2 (IGFBP2) was assessed using the immunoreactive score (IRS). Repeated internal cross-validation was performed to examine the statistical validity of the cut off points for all biomarkers. Results: After a median follow-up time of 105.4 months, overall 370 women (36.2%) had relapsed and 270 (26.4%) had died. Tumors expressing IGF1R-alpha above the median IRS were significantly more frequently HR positive (luminal A+B+HER2), as compared to HER2-enriched and triple negative ones (p,0.001 for both comparisons). IGF2R was overexpressed significantly more frequently in HR negative tumors (p = 0.001) and had an inverse correlation with all other biomarkers. Patients with luminal A and B tumors with high IGF1R-alpha and negative EGFR expression (N = 190) had significantly higher 4-year survival rates, as compared to the rest (log-rank p = 0.046), as did patients with luminal A and B tumors with high IGF1R-alpha and low IGF2R expression, as compared to the rest (N = 91), (log-rank p = 0.035). After adjustment for significant variables, patients in the latter group had a relative 45% reduction in the risk of death, as compared to the rest (p = 0.035). Conclusion: Aberrant expression of components of the IGF1R pathway is associated with better clinical outcomes in women with luminal A and B, node positive, early breast cancer.