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The transforming growth factor-β (TGFβ) plays a dual role in breast cancer, acting as a tumor suppressor in early carcinomas while promoting tumor metastasis in more advanced breast carcinoma. As a result, the prognostic role of TGFβ and its signaling components in breast cancer remains unclear. Here we evaluated the expression levels of TGFβ signaling receptors TβRII and TβRI using human breast cancer tissue microarrays and a large publicly available gene profiling database in relation to various clinicopathological parameters. Our results indicate that breast cancer tissues express lower TβRII and TβRI protein levels compared with normal breast tissue. In contrast to TβRI expression, TβRII mRNA expression levels were also significantly downregulated in invasive breast cancer compared with normal breast tissue (4.18-fold downregulation, P=9.3×10 -115 ). Interestingly, within the cancer cases analyzed, our results revealed a direct correlation between high TβRII and TβRI expression levels and classic poor prognostic clinicopathological parameters, including larger tumor size, advanced tumor stage, and poorly differentiated tumors. Next, we examined TGFβ receptors' expression in relation to breast cancer molecular subtypes. Importantly, our results revealed that whereas expression of TGFβ receptors in luminal A and triple-negative breast cancer showed no correlation with patient outcome, their expression in luminal B and HER2 subtypes showed significant association with favorable patient outcome. Together, these results indicate that although TGFβ receptors are downregulated in breast cancer, their expression in tumors is an indicator of aggressive breast cancer phenotype. Moreover, the relation between TGFβ pathway and patient outcome is breast cancer subtype dependent., (Copyright © 2016. Published by Elsevier Inc.)

Background: A new diagnostic and prognostic biomarker may be of value in cancer diseases. Our study aimed to evaluate the CDKN1A/p21 and TGFBR2 level measurable in a cohort of patients with breast cancer after mastectomy, and to confirm their suitability to serve as prognostic biomarkers of the cancer., Methods: The expression levels of CDKN1A/p21 and TGFBR2 were detected by reverse transcription-PCR (RT-PCR), western blot assay and immunohistochemical staining for 65 primary tumor samples and paired adjacent noncancerous breast tissues. Their relations to clinicopathologic parameters and to the prognosis of patients with breast cancer were analyzed., Results: We found the mRNA and protein expression levels of CDKN1A/p21 were significantly upregulated in breast cancer tissues compared with adjacent nontumorous breast tissues. Increased CDKN1A/p21 expression showed a significant correlation with larger tumor size (P=0.014), higher tumor dedifferentiation grade (P=0.021), lymph node metastasis (P=0.019) and a shorter disease-free survival (P=0.044). Contrarily, the expression levels of TGFBR2 mRNA and protein were significantly decreased in breast cancer tissues compared with adjacent nontumorous breast tissues. Underexpression of TGFBR2 in breast cancer was correlated with larger tumor size (P=0.034), lymph node metastasis (P=0.039) and a shorter disease-free survival (P=0.035). Statistical analysis suggested that there was no significant association between CDKN1A/p21 and TGFBR2 expression., Conclusions: in summary, our results suggested that high CDKN1A/p21 and low TGFBR2 expression was closely correlated with adverse pathological parameters and poor prognosis in breast cancer. Both CDKN1A/p21 and TGFBR2 are presented as possible candidates for breast cancer biomarkers.

Surface-enhanced Raman scattering (SERS) technique is becoming highly popular for multiplex biosensing due to the 'fingerprint' Raman spectra from every molecule. As a proof-of-concept, we demonstrated the actively targeted multiplex in vitro and in vivo detection of three intrinsic cancer biomarkers - EGFR, CD44 and TGFβRII in a breast cancer model using three multiplexing capable, biocompatible SERS nanoparticles/nanotags. Intra-tumorally injected antibody conjugated nanotags specifically targeting the three biomarkers exhibited maximum signal at 6 hours and no detectable signal at 72 hours. However, nanotags without antibodies showed no detectable signal after 6 hours. This difference could be due to the specific binding of the bioconjugated nanotags to the receptors on the cell surface. Thus, this study establishes SERS nanotags as an ultrasensitive nanoprobe for the multiplex detection of biomarkers and opens up its potential application in monitoring tumor progression and therapy and development into a theranostic probe.

Unlabelled: Encapsulated papillary carcinoma (EPC) of the breast is a distinct histological subtype characterised by malignant epithelial proliferation supported by fibrovascular stalks. Although EPC typically lacks myoepithelial cells, it shows indolent clinical course. The classification of EPC as an in situ, or invasive disease, remains a matter of debate., Methods: In this study, the authors investigated a panel of invasion-associated markers in a series of EPC and compared their expression with control groups of non-papillary ductal carcinoma in situ (DCIS) and conventional invasive carcinomas. The expression pattern of four matrix metalloproteinases (MMP-1, MMP-2, MMP-7 and MMP-9), transforming growth factor receptor beta, vascular endothelial growth factor (VEGF) and E-cadherin were assessed in the tumour cell and/or stromal tissue, and the results were analysed., Results: EPC showed higher expression levels of both MMP-1 and MMP-9 compared with DCIS, and no significant differences were observed between EPC and invasive carcinoma. Expression of MMP-2 and MMP-7 levels were similar in EPC and DCIS, but both showed lower levels compared with invasive tumours. EPC showed higher expression of E-cadherin and transforming growth factor receptor ß1 compared with both DCIS and invasive cancer. No difference in the stromal expression of MMPs or tumour expression of VEGF was detected., Conclusion: EPC exhibits an expression pattern of invasion-associated markers, which is intermediate in nature between DCIS and invasive cancer, providing further support of the unique biological features of EPC, and which may explain its clinically indolent behaviour.

Head and neck cancers, especially laryngeal carcinoma, are still an essential therapeutic problem worldwide. The most common risk factors which participate in initiation of cancer progression are tobacco smoking and alcohol abuse. The fundamental factor which confines effective therapy is tumor advanced stage at the moment of diagnosis. For proper determination of cancer progression there still is a need to identify new markers which can describe cancer cells and are also related in invasiveness and tumor matrix rebuild. The studies were performed on tissue samples divided in two groups: from patient who smoked less and above 20 cigarettes a day. We observed the expression of studied antigens as follows: MMP-2 in 100%, TGF-beta1 in 86% and TGF-betaRI in 79% cases. In tumor stroma we observed higher expression of MMP-2, TGF-beta1 in patients with higher exposure to tobacco smoke. Moreover in patients who smoked above 20 cigarettes, we detected higher expression of MMP-2 in tumor stroma (86% vs. 12.5%), compared with expression in cancer cells (3% vs. 3.25%). Expression of TGF-betaRI, in group I, was respectively higher in tumor stroma (16.8%) compared with cancer cells (6%). However we've found no expression of TGF-BRI in samples from patients smoking more then 20 cigarettes a day. In summary we may suggest, that the level of exposure on tobacco smoke play important role on changes in tumor markers expression.

Background: Analysis of the early molecular abnormalities that play an oncogenic role in the progression of pulmonary neoplasia may lead to the identification of useful markers for early detection and prognosis. In normal squamous epithelium, transforming growth factor beta (TGFbeta) regulates cell growth and differentiation via specific membranous receptors and intracellular signaling molecules (Smads). The authors previously observed that, in head and neck squamous cell carcinoma, the expression of the TGFbeta type II receptor (TbetaR-II) decreases as tumors become less differentiated and more biologically aggressive., Methods: In this pilot study of 48 premalignant bronchoepithelial lesions, the authors evaluated the expression of TbetaR-II and 2 proliferation markers (Ki-67 and MCM2), and the amount of early DNA fragmentation as evidence of apoptosis., Results: The authors observed that the progression of premalignant lesions toward carcinoma in situ is accompanied by a decrease in TBR II expression and apoptosis and an increase in the expression of Ki-67 and MCM2., Conclusions: These results suggested that the TGFbeta pathway may be impaired early in the neoplastic process and that a combination of selected markers can provide a useful profile to detect preneoplastic changes in individuals at high risk for developing pulmonary carcinoma.

Objective: Pheochromocytomas are uncommon tumours arising from chromaffin cells of the adrenal medulla and related paraganglia. So far, one of the few reported markers to discriminate malignant from benign tumours is the betaB-subunit of inhibin and activin, members of the transforming growth factor (TGF)-beta superfamily of growth and differentiation factors., Design: We investigated the expression of the mRNAs coding for activin and inhibin subunits, their receptors and binding proteins by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) and studied the presence of the inhibin betaB-subunit in human pheochromocytomas by immunohistochemistry., Patients: Samples from resected pheochromocytomas of patients operated between 1973 and 2003 were used for experiments., Results: The immunohistochemical investigations revealed that staining of the inhibin betaB-subunit was positive in 12 of 36 (33%) benign and 5 of 34 (15%) malignant pheochromocytomas (P > 0.05). Therefore, it was not possible to discriminate between benign and malignant tumours solely on the basis of inhibin betaB-subunit immunohistochemistry. Quantitative real-time RT-PCR in nine benign and four malignant tumours showed expression of inhibin alpha-, betaA- and betaB-subunits, the activin receptors Alk-4, ActRIIA, and ActRIIB, and the inhibin- and activin-binding proteins betaglycan and follistatin in all samples. No correlations were detected between individually coupled expression of mRNAs of these activin- and inhibin-related genes in the 13 pheochromocytomas. Only inhibin betaA-subunit expression was different in malignant compared to benign pheochromocytomas (P = 0.020)., Conclusions: No clear role for activin and inhibin was found in discriminating between benign and malignant pheochromocytomas.

The mechanisms of colonization and growth of metastatic liver tumors from colorectal cancers remain obscure. Forty-three resected colorectal metastatic liver tumors with surrounding livers were evaluated for apoptotic index (AI), proliferation index (PI), and immunohistochemical expressions of TGF-beta1. TGF-beta receptor II, Fas, and Fas-ligand. All the parameters were significantly higher in the peri-tumoral livers than in the tumors with the exception of PI, which was significantly high in tumors. Enhanced TGF-beta1 expression was noticed at the interface between the metastatic tumor and the adjacent liver parenchyma. The AIs of hepatocytes in the TGF-beta1-positive areas (8.7 +/- 7.5%, n = 43) were significantly higher when compared with those in the TGF-beta1-negative areas (2.4 +/- 4.5%, n = 42) (p < 0.001). However, the same kind of correlation could not be found in metastatic tumors. The enhanced expression of TGF-beta1 and hepatocyte apoptosis in the peri-tumoral liver parenchyma may suggest that TGF-beta1 plays a substantial role in the development of colorectal liver metastasis.

Background: The Amsterdam criteria are used worldwide for the clinical diagnosis of hereditary nonpolyposis colorectal carcinoma (HNPCC). In Japan, clinical criteria (JCC) have been proposed to identify as many HNPCC cases as possible, but the suitability of the JCC remains uncertain. In this article, the authors evaluate retrospectively whether the JCC are adequate to diagnose HNPCC compared with the Bethesda guidelines (BG) and also investigated useful screening methods for HNPCC., Methods: The authors studied 452 colorectal carcinoma cases, of which 69 cases fulfilled the JCC (A, 12; B, 57) and 106 fulfilled the BG. Microsatellite instability (MSI) was examined for 452 cases. TGF beta RII, immunohistochemical staining, and germline mutations of hMLH1 and hMSH2 were analyzed in high-frequency MSI cases., Results: High-frequency MSI was found in 21.7% (98 of 452). Germline mutations were detected in eight cases (hMLH1, three, hMSH2; five). Six cases fulfilled the JCC (A, four; B, two), and six fulfilled the BG. The germline mutation rate was significantly higher in the JCCA than in non-JCCA cases (33.3% vs. 0.91%; P < 0.001) and in cases with an age at onset younger than 50 years than older than 50 years (9.3% vs. 0.27%, P < 0.001). All germline mutation carriers had the TGF beta RII mutation. Immunohistochemically, a decreased nuclear staining was found in 57.3% (47 of 82) for hMLH1 and in 18.3% (15 of 82) for hMSH2. The frequency of predicted germline mutations was higher in cases with decreased hMSH2 than hMLH1 (33.3% vs. 6.4%; P = 0.016)., Conclusions: The JCCA are suitable for selecting cases to analyze for gene mutations, but the JCCB are not useful for the clinical setting. The authors suggest that an age at onset younger than 50 years is also important for screening. Analyzing TGF beta RII mutations and immunohistochemical staining of hMLH1 or hMSH2 for cases with MSI phenotype are useful for selecting cases who should be tested for germline mutations., (Copyright 2002 American Cancer Society. DOI 10.1002/cncr.10332)

Objective: To investigate the role of cell cycle regulators in the pathogenesis of papillary carcinoma of the thyroid., Design: Resistance to transforming growth factor beta-mediated inhibition is a well-known pathogenic mechanism in epithelial neoplasias. In a retrospective study, the expression of transforming growth factor beta receptors types I and II, cyclin D1, and the cyclin-dependent inhibitor p27kip, was analyzed by immunohistochemistry. Results were interpreted in the context of clinicopathological data. Patient follow-up ranged from 1 to 18 years, with a mean of 4 years., Materials: Twenty conventional primary papillary carcinomas and their metastases were selected according to current pathologic criteria. Nonconventional papillary carcinomas (eg, tall-cell, columnar) were excluded from the analysis., Results: Cyclin D1 was expressed more intensely in the tumor than in adjacent nonneoplastic parenchyma. Within a given tumor, however, there was significant heterogeneity in expression intensity and percentage of positive cells, particularly in metastases. Type I receptors were strongly expressed in 90% of tumors, while 80% of the tumors revealed low to no expression of type II receptors. In 10% of tumors, type I receptors were absent and type II receptors expressed. Simultaneous absence of both receptors was not observed. While p27kip was strongly expressed in nonneoplastic thyroid, it was not detected in any of the primary tumors or their metastases., Conclusions: The results strongly suggest that functional abnormalities in type II receptors result in increased levels of cyclin D1 and down-regulation of p27kip. This would maintain cells in a proliferative state and would promote tumor progression.

The distribution of the three mammalian isoforms of transforming growth factor (TGF)-beta (TGF-beta 1, -beta 2, and -beta 3) as well as their signaling receptors, TGF-beta type I and type II receptors (T beta R-I and T beta R-II, respectively), in gastric carcinoma tissue was examined by immunohistochemistry using specific antibodies. Tissue specimens were obtained from 25 cases of gastric carcinoma, which were classified into two groups according to Lauren's classification, i.e. 15 cases of diffuse carcinoma and 10 cases of intestinal carcinoma. In normal gastric mucosa apart from carcinoma nests, all of TGF-beta 1, -beta 2, -beta 3, T beta R-I and T beta R-II were clearly demonstrated in fundic glands. In sharp contrast, none of them was detectable in surface mucous cells. In carcinoma cells, strong staining for TGF-beta 1, -beta 2 and -beta 3 was obtained only in diffuse-type carcinoma. In particular, carcinoma cells scattered as single cells or small nests had a tendency to show strong staining for TGF-betas. The receptors tended to be distributed concomitantly with the ligands, and diffuse-type carcinoma showed stronger receptor staining than intestinal-type carcinoma. In cancer stroma, TGF-betas and receptors were detected in both diffuse and intestinal types, but the area with positive staining was wider and more dispersed in diffuse-type carcinoma than in intestinal carcinoma. These results suggest that TGF-beta may contribute in part to the variety of histogenesis and mode of progression of gastric carcinoma.