Absence of transforming growth factor-β type II receptor is associated with poorer prognosis in HER2-negative breast tumours

Paiva, Carlos Eduardo; Drigo, Sandra A.; Rosa, Francisco Dalla; Neto, Francisco A. Moraes; Caldeira, José Roberto Fígaro; Soares, Fernando Augusto; Domingues, Maria Aparecida Custódio; Rogatto, Sílvia Regina

doi:10.1093/annonc/mdp518

Cited by 22 publications

(19 citation statements)

References 24 publications

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“…HER2 expression was considered as positive (score 3+) and negative (score 0-1+). Samples with a score of 2+ were excluded from the analysis (15). This study was approved by the Academic Advisory Board of Soochow University.…”

Section: Study Participantsmentioning

confidence: 99%

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

Zhang¹,

Guo²,

Cheng³

et al. 2011

Oncology Letters

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Abstract.Little is known about the correlation between TGFBR2 G-875A and breast cancer risk. Moreover, the associations of the expression of estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2) in breast cancer tissues with the TGFB1 C-509T, T+29C and TGFBR2 G-875A polymorphisms remain to be determined. In this study, we genotyped for TGFB1 C-509T, T+29C and TGFBR2 G-875A in fresh surgically resected tissues (n=82) and archived paraffin-embedded specimens (n=88) from 170 patients with breast cancer, as well as peripheral blood samples from 178 cancer-free female individuals. Evaluation of ER, PR and HER2 expression was performed using immunohistochemical staining. Logistic regression analysis was carried out to determine the risk of breast cancer by calculating the odds ratios (ORs) and their 95% confidence intervals (CIs). As a result, no difference was observed in the TGFB1 C-509T, T+29C genotype and allele frequencies between patients and controls. However, the frequency of the TGFBR2 -875A allele was marginally higher in cancer-free female individuals than that of women with breast cancer (24.2 vs. 17.9%, P=0.05). Notably, when stratification was performed by ER, PR and HER2 expression, the TGFBR2 -875A allele was found to correlate significantly to a decreased risk of breast cancer with ER + (OR=0.57, 95% CI 0.

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Section: Study Participantsmentioning

confidence: 99%

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

Zhang¹,

Guo²,

Cheng³

et al. 2011

Oncology Letters

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“…It binds with a high affinity to TGF-β type II receptor (TGF-β-RII), which transactivates TGF-β type I receptor to initiate an intracellular signaling cascade by bringing about phosphorylation of 2 receptorregulated Smads (Smad2 and 3), recruiting the common-partner Smad (Smad4) to form the Smad4-Smad2/3 complexes, and translocating to the nucleus as the transcription factor to regulate expression of target genes (4). Thus far, the clinical prognostic role of TGF-β pathway components in human breast cancer remains elusive, which may be due to the complexity introduced by a variety of other molecules and systemic factors, such as estrogen receptor α and human epidermal growth factor receptor 2 status, common-partner and inhibitory Smads, early-age onset, and menopausal status (1,(5)(6)(7)(8)(9)(10)(11). While several studies have been published on the prognostic role of pathway components such as TGF-β receptors, Smad2/3, and other regulatory molecules, their results conflict with respect to the association of cancer survival with expression of TGF-β-RII (7-9) and pSmad2/3 and pSmad4 in breast cancer cells (11,12).…”

mentioning

confidence: 99%

Associations of the Transforming Growth Factor β/Smad Pathway, Body Mass Index, and Physical Activity With Breast Cancer Outcomes: Results From the Shanghai Breast Cancer Study

Su¹,

Cai²,

Zheng³

et al. 2016

Am. J. Epidemiol.

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The transforming growth factor β (TGF-β) pathway plays an important role in breast cancer progression and in metabolic regulation and energy homeostasis. The prognostic significance of TGF-β interaction with obesity and physical activity in breast cancer patients remains unclear. We evaluated the expression of TGF-β type II receptor and pSmad2 immunohistochemically in breast cancer tissue from 1,045 patients in the Shanghai Breast Cancer Study (2002)(2003)(2004)(2005). We found that the presence of nuclear pSmad2 in breast cancer cells was inversely associated with overall and disease-free survival, predominantly among participants with lower body mass index (BMI; weight (kg)/height (m) 2 ) and a moderate level of physical activity. However, the test for multiplicative interaction produced a significant result only for BMI (for disease-free survival and overall survival, adjusted hazard ratios were 1.79 and 2.05, respectively). In 535 earlier-stage (T1-2, N0) invasive cancers, nuclear pSmad2 was associated with improved survival among persons with higher BMI (overall survival: adjusted hazard ratio = 0.27, 95% confidence interval: 0.09, 0.86). The cytoplasmic pattern of TGF-β type II receptor expression in cancer cells was significantly associated with a lower survival rate but was not modified by BMI or physical activity. Our study suggests that the TGF-β pathway in tumor cells is involved in breast cancer prognosis and may be modified by BMI through pSmad2. body mass index; breast cancer; physical activity; pSmad2; survival; TGF-β pathway; TGF-β type II receptor; transforming growth factor β Abbreviations: BMI, body mass index; CI, confidence interval; HR, hazard ratio; MET, metabolic equivalent of task; TGF-β, transforming growth factor β; TGF-β-RII, transforming growth factor β type II receptor; TNBC, triple-negative breast cancer; TNM, tumor-node-metastasis.

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“…Whereas, it was shown in this study that higher TGFBR2 mRNA expression was associated with better relapse-free survival for patients with negative lymph node status ( Figure 5-4 B). This finding was more in agreement with Paiva et al's study which showed that TβRII down-expression was significantly associated with breast cancer and the absence of TβRII was an adverse prognostic factor [163]. Patients from the TCGA cohort (A) and GEO cohort (B) were divided into three groups (low, mid and high) according to their tumour levels of TGFB1, TGFB2, TGFB3, TGFBR1 or TGFBR2 mRNA.…”

Section: Associations Between the Mrna Levels And The Patients' Clinisupporting

confidence: 89%

“…Thus the association between the expression levels and the patients' clinical outcome may serve as an indicator of the proportion of the three types of tumours. The conflicting results such as that were reported for the associations between the protein levels of TGFβ1 and TβRII and the patients' clinical outcomes [161][162][163][164], were very likely due to that the studied cohorts were composed of different proportions of the three types of tumours.…”

Section: Discussionmentioning

confidence: 91%

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Cytotoxicity of ascorbate to cancer cells: mathematical modelling, mechanisms and clinical implications

Chen¹

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Studies over the last few decades provided supportive evidence for further research on the use of intravenous administration of high-dose ascorbate (0.5 -1.5 grams per kilogram of body weight) in cancer treatment. Although intravenous ascorbate showed limited anticancer activity in the recent clinical trials, its potential beneficial effects were noted, such as improvement in quality of life, reduction of chemotherapy-associated toxicity, reduction of inflammation and stabilization of cancer progression. These observations were in agreement with the outcomes of three cancer patients who declined chemotherapy and received intravenous ascorbate as an alternative in a preliminary clinical case study (Chapter 4). It was commonly accepted that the cytotoxicity of ascorbate was mediated by hydrogen peroxide (H2O2). However, our analysis and interpretation of the published results were not consistent with this being the sole mechanism of cytotoxicity, and an additional dehydroascorbate-mediated mechanism was proposed in this thesis (Chapter 1).In order to have a holistic understanding of the differential effects of ascorbate treatment in in vitro, animal and human studies, the treatment-induced changes in the intracellular H2O2 concentrations of the targeted cells should be compared. However, precise measurement of intracellular H2O2concentrations in vivo is difficult. In Chapter 2, a mathematical model was established for estimating the extracellular and intracellular H2O2 concentrations in a biological system that was challenged with H2O2 and/or an agent that could induce H2O2 production (such as ascorbate). Simulation of the mathematical model was carried out with the values of variables estimated from the published scientific literature and the experimental data obtained from this study. Several predictions were made and validated with the experimental results. One simulation predicted a limited increase of intracellular H2O2 concentration in a typical intravenous ascorbate treatment, which should be insufficient to induce cell death in tumours. The mathematical model also provided methods for estimating intrinsic intracellular H2O2 production rate and intracellular H2O2 concentration based on extracellular H2O2 concentration and other cell-dependent parameters, which were easier to be obtained with the current experimental methods.In Chapter 3, it was demonstrated in vitro that the cytotoxicity of ascorbate was mediated by both H2O2 and dehydroascorbate (DHA). The associations between the responses of cells to ascorbate (0 -30 mM) and some extracellular, cellular and molecular variables, such as cell culture medium, serum, glucose, pyruvate, cell cycle, cell volume and the expression and activities of H2O2 ii decomposing enzymes catalase and glutathione peroxidase, were investigated. Pyruvate but not glucose showed protective effect on cells in DHA treatment. Increased oxygen reactive species (ROS) levels in the DHA-treated cells was observed. These results supported our hypothesis that DHA might be able t...

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Absence of transforming growth factor-β type II receptor is associated with poorer prognosis in HER2-negative breast tumours

Cited by 22 publications

References 24 publications

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

A functional polymorphism of TGFBR2 is associated with risk of breast cancer with ER+, PR+, ER+PR+ and HER2− expression in women

Associations of the Transforming Growth Factor β/Smad Pathway, Body Mass Index, and Physical Activity With Breast Cancer Outcomes: Results From the Shanghai Breast Cancer Study

Cytotoxicity of ascorbate to cancer cells: mathematical modelling, mechanisms and clinical implications

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