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1.
Radiology ; 308(2): e222646, 2023 08.
Article in English | MEDLINE | ID: mdl-37526540

ABSTRACT

Background Half of breast cancers exhibit low expression levels of human epidermal growth factor receptor 2 (HER2) and can be targeted by new antibody-drug conjugates. The imaging differences between HER2-zero (immunohistochemistry [IHC] score of 0), HER2-low (IHC score of 1+ or 2+ with negative findings at fluorescence in situ hybridization [FISH]), and HER2-positive (IHC score of 2+ with positive findings at FISH or IHC score of 3+) breast cancers were unknown. Purpose To assess whether multiparametric dynamic contrast-enhanced MRI-based radiomic features can help distinguish HER2 expressions in breast cancer. Materials and Methods This study included women with breast cancer who underwent MRI at two different centers between December 2020 and December 2022. Tumor segmentation and radiomic feature extraction were performed on T2-weighted and dynamic contrast-enhanced T1-weighted images. Unsupervised correlation analysis of reproducible features and least absolute shrinkage and selector operation were used for the selection of features to build a radiomics signature. The area under the receiver operating characteristic curve (AUC) was used to assess the performance of the radiomic signature. Multivariable logistic regression was used to identify independent predictors for distinguishing HER2 expressions in both the training and prospectively acquired external data set. Results The training set included 208 patients from center 1 (mean age, 53 years ± 14 [SD]), and the external test set included 131 patients from center 2 (mean age, 54 years ± 13). In the external test data set, the radiomic signature achieved an AUC of 0.80 (95% CI: 0.71, 0.89) for distinguishing HER2-low and -positive tumors versus HER2-zero tumors and was a significant predictive factor for distinguishing these two groups (odds ratio = 7.6; 95% CI: 2.9, 19.8; P < .001). Among HER2-low or -positive breast cancers, histology type, associated nonmass enhancement, and multiple lesions at MRI had an AUC of 0.77 (95% CI: 0.68, 0.86) in the external test set for the prediction of HER2-positive versus HER2-low cancers. Conclusion The radiomic signature and tumor descriptors from multiparametric breast MRI may predict distinct HER2 expressions of breast cancers with therapeutic implications. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Kataoka and Honda in this issue.


Subject(s)
Breast Neoplasms , Multiparametric Magnetic Resonance Imaging , Humans , Female , Middle Aged , Multiparametric Magnetic Resonance Imaging/methods , Breast Neoplasms/pathology , In Situ Hybridization, Fluorescence , Magnetic Resonance Imaging/methods , Breast/pathology , Retrospective Studies
2.
Clin Cancer Res ; 25(22): 6731-6741, 2019 11 15.
Article in English | MEDLINE | ID: mdl-31515462

ABSTRACT

PURPOSE: High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC. EXPERIMENTAL DESIGN: We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group. RESULTS: Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (P Interaction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = -0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02-1.06; P = 0.001), but not in luminal tumors or TNBCs (P Interaction = 0.04). CONCLUSIONS: The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.


Subject(s)
Breast Neoplasms/etiology , Breast Neoplasms/pathology , Lymphocytes, Tumor-Infiltrating/immunology , Lymphocytes, Tumor-Infiltrating/pathology , Tumor Microenvironment/immunology , Adult , Aged , Biomarkers, Tumor , Breast Neoplasms/drug therapy , Breast Neoplasms/mortality , Chemotherapy, Adjuvant , Female , Humans , Lymphocyte Count , Lymphocytes, Tumor-Infiltrating/metabolism , Middle Aged , Neoadjuvant Therapy , Neoplasm Grading , Neoplasm Staging , Prognosis , Retreatment , Treatment Outcome , Tumor Microenvironment/genetics
3.
Blood Cells Mol Dis ; 75: 1-10, 2019 03.
Article in English | MEDLINE | ID: mdl-30502564

ABSTRACT

Primary CNS lymphomas (PCNSL) are rare and poor prognosis diffuse large B-cell lymphomas. Because of the brain tumor environment and the restricted distribution of drugs in the CNS, specific PCNSL patient-derived orthotopic xenograft (PDOX) models are needed for preclinical research to improve the prognosis of PCNSL patients. PCNSL patient specimens (n = 6) were grafted in the caudate nucleus of immunodeficient nude mice with a 83% rate of success, while subcutaneous implantation in nude mice of human PCNSL sample did not generate lymphoma, supporting the role of the brain microenvironment in the PCNSL physiopathology. PDOXs showed diffuse infiltration of B-cell lymphoma cells in the brain parenchyma. Each model had a unique mutational signature for genes in the BCR and NF-κB pathways and retained the mutational profile of the primary tumor. The models can be stored as cryopreserved biobank. Human IL-10 levels measured in the plasma of PCNSL-PDOX mice showed to be a reliable tool to monitor the tumor burden. Treatment response could be measured after a short treatment with the targeted therapy ibrutinib. In summary, we established a panel of human PCNSL-PDOX models that capture the histological and molecular characteristics of the disease and that proved suitable for preclinical experiments. Our methods of generation and characterization will enable the generation of additional PDOX-PCNSL models, essential tools for cognitive and preclinical drug discovery.


Subject(s)
Central Nervous System Neoplasms/pathology , Disease Models, Animal , Heterografts/pathology , Lymphoma, Large B-Cell, Diffuse/pathology , Adenine/analogs & derivatives , Animals , Caudate Nucleus , Heterografts/drug effects , Humans , Interleukin-10/analysis , Mice , Mice, Nude , Piperidines , Prognosis , Pyrazoles/therapeutic use , Pyrimidines/therapeutic use , Tumor Burden
4.
Mod Pathol ; 31(1): 68-82, 2018 01.
Article in English | MEDLINE | ID: mdl-28884749

ABSTRACT

Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.


Subject(s)
Breast Neoplasms/genetics , Breast Neoplasms/pathology , Carcinoma, Neuroendocrine/genetics , Carcinoma, Neuroendocrine/pathology , Adult , Aged , Aged, 80 and over , Breast Neoplasms/mortality , Carcinoma, Neuroendocrine/mortality , DNA Mutational Analysis , Female , Humans , Kaplan-Meier Estimate , Middle Aged , Prognosis , Proportional Hazards Models
6.
Mol Imaging Biol ; 18(4): 617-26, 2016 08.
Article in English | MEDLINE | ID: mdl-26630973

ABSTRACT

PURPOSE: Transgenic mice expressing the polyoma middle T oncoprotein (PyMT) in the mammary epithelium were explored by multimodal imaging to monitor longitudinally spontaneous tumor growth and response to chemotherapy. PROCEDURES: Positron emission tomography (PET) with 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) and 3'-deoxy-3'-[(18)F]fluorothymidine ([(18)F]FLT), single photon emission tomography (SPECT) with [(99m)Tc]TcO4 ([(99m)Tc]TEC), X-ray computed tomography, and fluorescent confocal endomicroscopy (FCE) images were acquired during tumor progression in female PyMT mice. Imaging with [(18)F]FDG and [(99m)Tc]TEC was also performed in untreated, doxorubicin-treated, and docetaxel-treated PyMT mice. Total tumor volumes were quantified. Tumors were collected and macroscopic and histological examinations were performed. RESULTS: All PyMT mice developed multifocal tumors of the mammary epithelium that became palpable at 8 weeks of age (W8). Computed tomography (CT) detected tumors at W14, while a clear tumoral uptake of [(99m)Tc]TEC and [(18)F]FDG was present as early as W6 and W8, respectively. No contrast between mammary tumors and surrounding tissue was observed at any stage with [(18)F]FLT. FCE detected an angiogenic switch at W10. Lung metastases were not clearly evidenced by imaging. Doxorubicin and docetaxel treatments delayed tumor growth, as shown by [(18)F]FDG and [(99m)Tc]TEC, but tumor growth resumed upon treatment discontinuation. Tumor growth fitted an exponential model with time constant rates of 0.315, 0.145, and 0.212 week(-1) in untreated, doxorubicin, and docetaxel groups, respectively. CONCLUSIONS: Molecular imaging of mammary tumors in PyMT is precocious, precise, and predictive. [(18)F]FDG-PET and [(99m)Tc]TEC SPECT monitor tumor response to chemotherapy.


Subject(s)
Antineoplastic Agents/therapeutic use , Carcinogenesis/pathology , Mammary Neoplasms, Animal/drug therapy , Multimodal Imaging/methods , Animals , Antineoplastic Agents/pharmacology , Cell Proliferation , Disease Models, Animal , Disease Progression , Female , Fluorescence , Fluorodeoxyglucose F18 , Ki-67 Antigen/metabolism , Mammary Neoplasms, Animal/blood supply , Mammary Neoplasms, Animal/diagnostic imaging , Mammary Neoplasms, Animal/pathology , Mice , Mice, Transgenic , Technetium/chemistry , Time Factors , Tomography, Emission-Computed, Single-Photon , Tomography, X-Ray Computed
7.
Acta Cytol ; 58(5): 427-31, 2014.
Article in English | MEDLINE | ID: mdl-25322776

ABSTRACT

OBJECTIVES: To describe cytology patterns in low-grade adenosquamous carcinomas (LGASCs) of the breast. STUDY DESIGN: Low-grade adenosquamous carcinomas of the breast are a recently described rare variant of primary metaplastic carcinomas characterized by clinical indolence, slow evolution and excellent survival. To date, only 7 cases of LGASC were studied cytologically, and it was demonstrated that LGASC identification was difficult because its cellular components exhibited unspecific and nonsuspicious features. They consisted of irregularly clustered cells without prominent cytonuclear atypia, mitosis or necrosis. The presence of metaplastic cells or keratin debris was helpful in accurate tumor typing. We report here 3 additional cases of LGASC that were initially studied by fine-needle aspiration. RESULTS: We have also encountered diagnostic difficulties and misdiagnosed tumors, since 2 cases were underdiagnosed as 'suspicious' and only 1 was accurately diagnosed as malignancy. CONCLUSION: The review of our cases and the literature confirms that, despite its putative metaplastic origin, LGASC is an entity which is difficult to diagnose using classical cytological methods. Moreover, core-needle biopsy as well as frozen sections may also misdiagnose LGASC as a benign breast lesion.


Subject(s)
Breast Neoplasms/pathology , Carcinoma, Adenosquamous/pathology , Mammary Glands, Human/pathology , Aged, 80 and over , Biopsy, Fine-Needle , Breast Neoplasms/diagnosis , Carcinoma, Adenosquamous/diagnosis , Female , Histocytochemistry , Humans , Middle Aged , Neoplasm Grading
8.
Breast J ; 17(2): 121-8, 2011.
Article in English | MEDLINE | ID: mdl-21306468

ABSTRACT

Neo-adjuvant chemotherapy of breast cancer provides an opportunity to evaluate predictive factors at initial tumor biopsy. We evaluated these factors on cell blocks obtained by diagnostic fine-needle cytopuncture (FNC), with respect to tumor regression and outcome. A prospective study (1996-2003, median follow-up 82 months) involved 163 patients with breast carcinoma (T2 ≥ 3 cm, T3, T4 noninflammatory) diagnosed by means of FNC. Malignancy, cytologic grade, and the presence of lymphocytes were determined on cytologic smears. Ki67, estrogen receptor (ER), progesterone receptor (PgR), HER2, and p53 expression was assessed on cell blocks by means of immunohistochemistry. All the patients received anthracycline-based chemotherapy. A combined clinical and pathologic tumor regression score was calculated. Twelve cases (7.5%) showed a complete regression, 72 cases (44%) a partial regression and 79 cases (48.5%) no regression. Factors predictive of regression were high grade, presence of lymphocytes, pN0, high Ki67 expression, hormone receptor negativity, and the "triple negative" phenotype. In univariate analysis 5-year metastasis-free survival rate (MFS) correlated with cytologic grade, pN, ER, and p53 status, while overall survival (OS) correlated with cytologic grade, type of surgery, pN, and ER status. In multivariate analysis, MFS was significantly influenced by the regression score, Ki67, age, ER status, pN, HER2, and initial tumor size. Except for age, the same parameters correlated with OS. FNC with the cell block technique is a rapid, minimally invasive, reliable, and inexpensive method for analyzing predictive biomarkers, and may thus be useful in the management of breast cancer patients requiring neo-adjuvant chemotherapy.


Subject(s)
Biomarkers, Tumor/analysis , Biomarkers/analysis , Breast Neoplasms/chemistry , Breast Neoplasms/drug therapy , Chemotherapy, Adjuvant , Phyllodes Tumor/chemistry , Phyllodes Tumor/drug therapy , Preoperative Care , Adolescent , Adult , Aged , Biopsy, Fine-Needle , Breast Neoplasms/pathology , Breast Neoplasms/surgery , Female , Follow-Up Studies , Humans , Mastectomy , Middle Aged , Phyllodes Tumor/pathology , Phyllodes Tumor/surgery , Predictive Value of Tests , Prognosis , Retrospective Studies , Treatment Failure , Young Adult
10.
Cancer ; 114(2): 111-7, 2008 Apr 25.
Article in English | MEDLINE | ID: mdl-18300231

ABSTRACT

BACKGROUND: Fine-needle aspiration generally produces results that are not as good for lobular carcinoma as the results for ductal carcinoma of the breast. In this study, the authors evaluated their team's performance in cytologic diagnosis of lobular carcinoma over 11 years and analyzed the reasons for diagnostic failure. METHODS: Cytologic findings were analyzed in 555 consecutive fine-needle cytopuncture specimens from women with palpable, invasive lobular carcinoma of the breast. The authors also examined the influence of the cytologist's experience, the clinical tumor size, the histologic subtype, and the histologic grade on diagnostic performance. All negative samples were re-examined, along with all samples that had been obtained during the last year of the study, to refine the morphologic description of lobular carcinoma. RESULTS: Malignancy was diagnosed in 68.8% of specimens overall. The individual pathologists diagnosed malignancy in from 44.4% to 81.1% of specimens, depending on their experience. Diagnostic performance was correlated with clinical tumor size, histologic grade, and histologic subtype, and correct diagnoses were significantly more frequent in pleomorphic subtypes than in "classic" types. Re-examination of all 32 negative specimens reduced the false-negative rate from 5.8% to 3.8%. CONCLUSIONS: Despite the pitfalls associated with lobular carcinoma of the breast, fine-needle cytopuncture remains a useful diagnostic tool before treatment. Failures can be reduced through experience and by better knowledge of cytologic features.


Subject(s)
Biopsy, Needle , Breast Neoplasms/pathology , Carcinoma, Ductal, Breast/pathology , Carcinoma, Lobular/pathology , Breast Neoplasms/surgery , Carcinoma, Ductal, Breast/surgery , Carcinoma, Lobular/surgery , False Negative Reactions , Female , Humans , Immunoenzyme Techniques
11.
Ann Thorac Surg ; 76(3): 896-902, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12963225

ABSTRACT

BACKGROUND: Proton nuclear magnetic resonance spectroscopy can be used to measure organic molecules in biological fluids. In this study, proton nuclear magnetic resonance spectroscopy of bronchoalveolar lavage was assessed to detect cellular damage in lung transplants. Also we evaluated a polyethylene glycol solution in lung preservation. METHODS: An isolated perfused and working pig lung was used to assess initial pulmonary function after in situ cold flush and cold storage for 6 hours in three preservation solutions: (1) Euro-Collins solution, (2) University of Wisconsin solution, and (3) low potassium solution with polyethylene glycol (PEG). Pulmonary vascular resistance and partial pressure of arterial oxygen were measured during reperfusion. Bronchoalveolar lavage was studied by proton nuclear magnetic resonance spectroscopy and a histologic study of the lungs was done at the harvest after ischemia and after reperfusion. RESULTS: Partial pressure of arterial oxygen and pulmonary vascular resistance were significantly better in PEG compared with Euro-Collins solution (p = 0.011). Interstitial edema was significantly higher in Euro-Collins solution (2.4 +/- 0.24; p = 0.02) and University of Wisconsin solution (2.7 +/- 0.20; p = 0.0003) than PEG (2 +/- 0.16). Mitochondria scale was better in PEG (8.1 +/- 0.46) than in Euro-Collins solution (6.2 +/- 0.37; p = 0.0001) or University of Wisconsin solution (5.6 +/- 1.36; p = 0.0046). In bronchoalveolar lavage proton nuclear magnetic resonance spectroscopy spectra, lactate, pyruvate, citrate, and acetate were only detected after reperfusion, with a significantly reduced production of acetate in PEG. Pyruvate was reduced at the limit of significance in PEG versus University of Wisconsin solution. CONCLUSIONS: Proton nuclear magnetic resonance spectroscopy seems to be a simple and suitable method for assessment of early injury to the lung transplant. In this experimental study, PEG preserved the lung better than University of Wisconsin solution and Euro-Collins solution in both the proton nuclear magnetic resonance spectroscopy study as well as the physiologic study.


Subject(s)
Lung Transplantation , Lung/metabolism , Magnetic Resonance Spectroscopy , Organ Preservation Solutions , Organ Preservation/methods , Polyethylene Glycols , Animals , Blood Gas Analysis , Swine , Time Factors
12.
Cardiovasc Res ; 59(1): 78-85, 2003 Jul 01.
Article in English | MEDLINE | ID: mdl-12829178

ABSTRACT

OBJECTIVES: Recent in vivo and in vitro studies in animals have demonstrated that cytokines of the IL-6 family are involved in cardiac hypertrophy and in protection of cardiomyocytes against apoptosis. The present study aims to analyse the capacity of human atrial cardiac cells (i.e., cardiomyocytes and fibroblasts) to display the gp130 receptor subunit, and to evaluate its functionality. METHODS: Twenty human atrial biopsies were used for immunohistochemistry, in situ hybridisation, and western blot analysis or dissociated for isolation and primary culture of cardiac cells. RESULTS: Fibroblasts present in tissue or maintained in primary culture clearly express gp130 whereas the signal in cardiomyocytes is weaker. Culture of cardiac cells with a gp130 agonist antibody enhances atrial natriuretic peptide (ANP), beta myosin heavy chain (beta-MHC) expression in cardiomyocytes, and significantly increases the cell surface area microm(2)). This process could involve STAT3 (signal transducer and activator of transcription 3) phosphorylation. CONCLUSIONS: These results demonstrate that gp130 activation in human cardiac cells leads to cardiomyocyte hypertrophy. We discuss several hypotheses on the role of IL-6-type cytokines on cardiomyocyte functions.


Subject(s)
Bacterial Proteins , Cardiomegaly/metabolism , Myocytes, Cardiac/metabolism , Receptors, Cytokine/analysis , Transcription Factors , Aged , Analysis of Variance , Antibodies, Blocking/pharmacology , Antigens, CD/immunology , Antigens, CD/metabolism , Antigens, CD/pharmacology , AraC Transcription Factor , Atrial Natriuretic Factor/analysis , Blotting, Western/methods , Cardiomegaly/pathology , Cell Size , Cells, Cultured , Cytokine Receptor gp130 , DNA-Binding Proteins/analysis , Fibroblasts/metabolism , Fluorescent Antibody Technique, Indirect , Heart Atria , Humans , Immunohistochemistry/methods , In Situ Hybridization/methods , Interleukin-6/immunology , Interleukin-6/metabolism , Membrane Glycoproteins/immunology , Membrane Glycoproteins/metabolism , Membrane Glycoproteins/pharmacology , Middle Aged , Myocytes, Cardiac/pathology , Myosin Heavy Chains/analysis , Phosphorylation , Quaternary Ammonium Compounds/pharmacology , Receptors, Cytokine/genetics , Receptors, Cytokine/immunology , Receptors, Interleukin-6/metabolism , Repressor Proteins/pharmacology , STAT3 Transcription Factor , Trans-Activators/analysis
13.
Ann Pathol ; 23(6): 496-507, 2003 Dec.
Article in French | MEDLINE | ID: mdl-15094588

ABSTRACT

Stereotactic 11-Gauge vacuum-assisted biopsy provides a valuable tool in the diagnosis of mammographically detected breast microcalcifications. However, this new diagnostic technology presents some limitations and requires a close collaboration between radiologists, pathologists and physicians. The aim of this work is to propose a practical approach in the management of large core biopsies and to summarize the different difficulties faced by the pathologist in the management and histological interpretation of specimens issuing from this device.


Subject(s)
Biopsy, Needle , Breast Diseases/pathology , Breast/pathology , Calcinosis/pathology , Biopsy, Needle/instrumentation , Breast Diseases/diagnosis , Breast Neoplasms/diagnosis , Breast Neoplasms/pathology , Calcinosis/diagnosis , Carcinoma in Situ/diagnosis , Carcinoma in Situ/pathology , Cicatrix/diagnosis , Cicatrix/pathology , Female , Fibrocystic Breast Disease/diagnosis , Fibrocystic Breast Disease/pathology , Humans , Mastectomy , Mucocele/diagnosis , Mucocele/pathology , Sclerosis , Specimen Handling , Vacuum
14.
J Clin Endocrinol Metab ; 87(7): 3279-86, 2002 Jul.
Article in English | MEDLINE | ID: mdl-12107237

ABSTRACT

Most of the TSH effects on the proliferation and differentiation of thyroid cells are mediated by cAMP via an adenylyl cyclase-activating Gs protein. TSH receptor responsiveness in cell cultures, is regulated by G protein-coupled receptor kinase (GRK) 2 and 5. To determine whether an alteration in activity and expression of GRKs might be associated with variable levels of TSH receptor desensitization in vivo, we studied human thyroid tissues including 21 normal tissues and 18 differentiated carcinomas. GRK activity was assayed by rhodopsin phosphorylation, and GRK protein and mRNA expressions assessed by immunoblotting and real-time quantitative RT-PCR, respectively. GRK2 and GRK5 were found as the predominant isoforms in the human thyroid. GRK5 protein expression was significantly decreased in differentiated thyroid carcinoma (P < 0.02) and paralleled a decrease in GRK mRNA expression (P < 0.02). In contrast, no difference in protein and mRNA levels of GRK2 were observed between normal and cancerous thyroid tissues. Although GRK2 protein levels correlated with GRK activities, we demonstrated a significant increase in GRK activity in differentiated thyroid carcinoma (P < 0.02). Less TSH receptor desensitization occurred in differentiated carcinoma than in normal thyroid tissue, as judged by TSH-stimulated cAMP response in human thyroid cells in primary culture. In conclusion, this study indicates that GRK2 activity and GRK5 expression have opposite regulations in cancer cells. Furthermore, the decrease in GRK5 expression may underlie the reduction in homologous desensitization of the TSH receptor in differentiated thyroid carcinoma, contributing to explain the increased cAMP levels in these tumors.


Subject(s)
Adenocarcinoma, Follicular/enzymology , Carcinoma, Papillary/enzymology , Carcinoma/enzymology , Cyclic AMP-Dependent Protein Kinases/metabolism , Protein Serine-Threonine Kinases/metabolism , Thyroid Neoplasms/enzymology , Adult , Aged , Cyclic AMP-Dependent Protein Kinases/genetics , Female , G-Protein-Coupled Receptor Kinase 2 , G-Protein-Coupled Receptor Kinase 3 , Humans , Male , Middle Aged , Protein Serine-Threonine Kinases/genetics , RNA, Messenger/metabolism , Receptors, Thyrotropin/metabolism , Reference Values , Thyroid Gland/enzymology , beta-Adrenergic Receptor Kinases
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