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1.
Int J Mol Sci ; 22(16)2021 Aug 17.
Artigo em Inglês | MEDLINE | ID: mdl-34445568

RESUMO

Tumor microenvironments shape aggressiveness and are largely maintained by the conditions of angiogenesis formation. Thus, endothelial cells' (ECs) biological reactions are crucial to understand and control the design of efficient therapies. In this work, we used models of ECs to represent a breast cancer tumor site as well as the same, healthy tissue. Cells characterization was performed at the transcriptome and protein expression levels, and the cells functional biological responses (angiogenesis and permeability) were assessed. We showed that the expression of proteins specific to ECs (ACE+, VWF+), their differentiation (CD31+, CD 133+, CD105+, CD34-), their adhesion properties (ICAM-1+, VCAM-1+, CD62-L+), and their barrier formation (ZO-1+) were all downregulated in tumor-derived ECs. NGS-based differential transcriptome analysis confirmed CD31-lowered expression and pointed to the increase of Ephrin-B2 and SNCAIP, indicative of dedifferentiation. Functional assays confirmed these differences; angiogenesis was impaired while permeability increased in tumor-derived ECs, as further validated by the distinctly enhanced VEGF production in response to hypoxia, reflecting the tumor conditions. This work showed that endothelial cells differed highly significantly, both phenotypically and functionally, in the tumor site as compared to the normal corresponding tissue, thus influencing the tumor microenvironment.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Mama/patologia , Células Endoteliais/patologia , Neovascularização Patológica/patologia , Transcriptoma , Biomarcadores Tumorais/genética , Mama/metabolismo , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Diferenciação Celular , Células Endoteliais/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Neovascularização Patológica/genética , Neovascularização Patológica/metabolismo , Microambiente Tumoral
2.
Medicine (Baltimore) ; 100(31): e26823, 2021 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-34397844

RESUMO

ABSTRACT: Low specificity and operator dependency are the main problems of breast ultrasound (US) screening. We investigated the added value of deep learning-based computer-aided diagnosis (S-Detect) and shear wave elastography (SWE) to B-mode US for evaluation of breast masses detected by screening US.Between February 2018 and June 2019, B-mode US, S-Detect, and SWE were prospectively obtained for 156 screening US-detected breast masses in 146 women before undergoing US-guided biopsy. S-Detect was applied for the representative B-mode US image, and quantitative elasticity was measured for SWE. Breast Imaging Reporting and Data System final assessment category was assigned for the datasets of B-mode US alone, B-mode US plus S-Detect, and B-mode US plus SWE by 3 radiologists with varied experience in breast imaging. Area under the receiver operator characteristics curve (AUC), sensitivity, and specificity for the 3 datasets were compared using Delong's method and McNemar test.Of 156 masses, 10 (6%) were malignant and 146 (94%) were benign. Compared to B-mode US alone, the addition of S-Detect increased the specificity from 8%-9% to 31%-71% and the AUC from 0.541-0.545 to 0.658-0.803 in all radiologists (All P < .001). The addition of SWE to B-mode US also increased the specificity from 8%-9% to 41%-75% and the AUC from 0.541-0.545 to 0.709-0.823 in all radiologists (All P < .001). There was no significant loss in sensitivity when either S-Detect or SWE were added to B-mode US.Adding S-Detect or SWE to B-mode US improved the specificity and AUC without loss of sensitivity.


Assuntos
Neoplasias da Mama , Mama , Aprendizado Profundo , Diagnóstico por Computador/métodos , Técnicas de Imagem por Elasticidade/métodos , Ultrassonografia Mamária/métodos , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Diagnóstico Diferencial , Detecção Precoce de Câncer/métodos , Feminino , Humanos , Interpretação de Imagem Assistida por Computador , Pessoa de Meia-Idade , Estudos Prospectivos , República da Coreia/epidemiologia , Sensibilidade e Especificidade
3.
Eur J Radiol ; 142: 109883, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34358810

RESUMO

In women with newly diagnosed breast cancer, preoperative staging is required to assess disease extent, enabling us to decide on the most optimal treatment strategy. For locoregional staging, assessment of intramammary tumor extent and presence of axillary and perhaps also internal mammary lymph node metastases is required. Due to the similarity in the underlying principle, contrast-enhanced mammography is increasingly considered instead of breast MRI for this purpose. When considering the combination of CEM and US as a single appointment imaging strategy for preoperative staging of breast cancer, there is only limited room for an additional benefit of breast MRI. For tumor size measurements, equal performance of both CEM and MRI are observed. Sensitivity of both techniques for detecting breast cancer is comparable, meaning that both techniques are capable of detecting additional ipsilateral or contralateral tumor foci. However, specificity is in favor of CEM, meaning that there is a slightly lower chance of having false positive findings in preoperative staging of the breast. Axillary US can be performed during the same appointment as CEM, with equal performance and limitations as evaluation of the axilla on standard breast MRI examinations. Finally, there is no need to actively pursue the detection of IMLN metastases, meaning that additional MRI to do so is not required. This review provides a 'pro-CEM' perceptive on the arguments why breast MRI is hardly necessary when CEM in combination with US has been performed as a single appointment imaging strategy in breast cancer patients.


Assuntos
Neoplasias da Mama , Axila/patologia , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Meios de Contraste , Feminino , Humanos , Imageamento por Ressonância Magnética , Mamografia , Estadiamento de Neoplasias , Sensibilidade e Especificidade
4.
Int J Mol Sci ; 22(14)2021 Jul 12.
Artigo em Inglês | MEDLINE | ID: mdl-34299089

RESUMO

The cytoskeletal protein vimentin is secreted under various physiological conditions. Extracellular vimentin exists primarily in two forms: attached to the outer cell surface and secreted into the extracellular space. While surface vimentin is involved in processes such as viral infections and cancer progression, secreted vimentin modulates inflammation through reduction of neutrophil infiltration, promotes bacterial elimination in activated macrophages, and supports axonal growth in astrocytes through activation of the IGF-1 receptor. This receptor is overexpressed in cancer cells, and its activation pathway has significant roles in general cellular functions. In this study, we investigated the functional role of extracellular vimentin in non-tumorigenic (MCF-10a) and cancer (MCF-7) cells through the evaluation of its effects on cell migration, proliferation, adhesion, and monolayer permeability. Upon treatment with extracellular recombinant vimentin, MCF-7 cells showed increased migration, proliferation, and adhesion, compared to MCF-10a cells. Further, MCF-7 monolayers showed reduced permeability, compared to MCF-10a monolayers. It has been shown that the receptor binding domain of SARS-CoV-2 spike protein can alter blood-brain barrier integrity. Surface vimentin also acts as a co-receptor between the SARS-CoV-2 spike protein and the cell-surface angiotensin-converting enzyme 2 receptor. Therefore, we also investigated the permeability of MCF-10a and MCF-7 monolayers upon treatment with extracellular recombinant vimentin, and its modulation of the SARS-CoV-2 receptor binding domain. These findings show that binding of extracellular recombinant vimentin to the cell surface enhances the permeability of both MCF-10a and MCF-7 monolayers. However, with SARS-CoV-2 receptor binding domain addition, this effect is lost with MCF-7 monolayers, as the extracellular vimentin binds directly to the viral domain. This defines an influence of extracellular vimentin in SARS-CoV-2 infections.


Assuntos
Neoplasias da Mama/patologia , Mama/patologia , Permeabilidade da Membrana Celular , Matriz Extracelular/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Vimentina/metabolismo , Mama/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Células Cultivadas , Feminino , Humanos , Domínios Proteicos , Glicoproteína da Espícula de Coronavírus/genética , Vimentina/genética
5.
Anticancer Res ; 41(7): 3607-3613, 2021 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-34230157

RESUMO

BACKGROUND/AIM: We evaluated timeliness of care at a safety-net hospital after implementation of a multidisciplinary breast program. PATIENTS AND METHODS: A prospective database of patients with breast cancer was created after multidisciplinary breast program initiation in 2018. Patients were tracked to obtain time to completion of diagnostic imaging, biopsy, and treatment initiation. Patients with breast cancer diagnosed from 2015-2017 were reviewed for comparison. RESULTS: A total of 102 patients were identified. There was no statistical difference in time to completion of imaging, biopsy, and initial treatment between the 2018 and the 2015-2017 cohorts (p>0.05). No statistical difference was observed in time to completion of imaging, biopsy, and initial treatment between different races (p>0.05). CONCLUSION: Within the same socioeconomic status, there was no differential delivery of screening, work-up, and treatment by race. Despite protocol implementations, efficiency of care remained limited in a safety-net hospital with lack of financial resources.


Assuntos
Neoplasias da Mama/diagnóstico , Idoso , Biópsia , Mama/patologia , Neoplasias da Mama/patologia , Gerenciamento de Dados/métodos , Feminino , Equidade em Saúde , Humanos , Programas de Rastreamento/métodos , Área Carente de Assistência Médica , Pessoa de Meia-Idade , Classe Social
6.
Nat Commun ; 12(1): 4413, 2021 07 20.
Artigo em Inglês | MEDLINE | ID: mdl-34285210

RESUMO

Enhanced neovasculogenesis, especially vasculogenic mimicry (VM), contributes to the development of triple-negative breast cancer (TNBC). Breast tumor-initiating cells (BTICs) are involved in forming VM; however, the specific VM-forming BTIC population and the regulatory mechanisms remain undefined. We find that tumor endothelial marker 8 (TEM8) is abundantly expressed in TNBC and serves as a marker for VM-forming BTICs. Mechanistically, TEM8 increases active RhoC level and induces ROCK1-mediated phosphorylation of SMAD5, in a cascade essential for promoting stemness and VM capacity of breast cancer cells. ASB10, an estrogen receptor ERα trans-activated E3 ligase, ubiquitylates TEM8 for degradation, and its deficiency in TNBC resulted in a high homeostatic level of TEM8. In this work, we identify TEM8 as a functional marker for VM-forming BTICs in TNBC, providing a target for the development of effective therapies against TNBC targeting both BTIC self-renewal and neovasculogenesis simultaneously.


Assuntos
Biomarcadores Tumorais/metabolismo , Proteínas dos Microfilamentos/metabolismo , Células-Tronco Neoplásicas/patologia , Neovascularização Patológica/patologia , Receptores de Superfície Celular/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/antagonistas & inibidores , Mama/patologia , Mama/cirurgia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Autorrenovação Celular/efeitos dos fármacos , Feminino , Humanos , Mastectomia , Camundongos , Proteínas dos Microfilamentos/antagonistas & inibidores , Pessoa de Meia-Idade , Células-Tronco Neoplásicas/efeitos dos fármacos , Neovascularização Patológica/tratamento farmacológico , Receptores de Superfície Celular/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/irrigação sanguínea , Neoplasias de Mama Triplo Negativas/terapia , Ensaios Antitumorais Modelo de Xenoenxerto
8.
Eur J Radiol ; 141: 109826, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-34174485

RESUMO

BACKGROUND: Atypical lesions found on percutaneous breast biopsy raise specific management issues. The aim of this study was to validate the previous performance of a decision tree defined by Forgeard et al to select a subset of patients at low-risk of surgical diagnostic upgrade that would be eligible for surveillance. METHODS: A consecutive series of 211 patients diagnosed with ADH on vacuum-assisted biopsy (VAB) of clustered microcalcifications alone, then operated in our institution, was reviewed. Histological findings on percutaneous cores were compared with definitive diagnoses on surgical specimens. The rate of cancer underestimation on VAB was analyzed in the four arms and two management attitudes defined in the scheme, using size and quality of microcalcification removal and the number of ADH foci. RESULTS: Ninety-eight women with ADH met the inclusion criteria. Overall, 20 cancers were diagnosed at surgery, showing a malignancy rate of 44% (17/39 patients) in the surgery group and of 5% (3/59 patients) in the surveillance group, which was not significantly different from the 2% rate in the monitored reference group (p > 0.64). The malignancy rate increased significantly with the size of clustered microcalcifications (0% when < 6mm, 17% when between 6mm and 21 mm, 48% when > 21 mm, p < 0001) and the number of ADH foci on VAB (14% when ≤ 2, 45% when > 2, p < 0.005). CONCLUSION: Our results corroborate - within the limits of large confidence intervals - those obtained with the reference decision tree. Due to statistical uncertainty, however, they need to be prospectively validated in a broader series.


Assuntos
Neoplasias da Mama , Calcinose , Carcinoma Intraductal não Infiltrante , Mama/diagnóstico por imagem , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Calcinose/diagnóstico por imagem , Calcinose/patologia , Carcinoma Intraductal não Infiltrante/patologia , Árvores de Decisões , Feminino , Humanos , Hiperplasia/patologia , Mamografia , Seleção de Pacientes , Estudos Retrospectivos
9.
Ann Plast Surg ; 86(6S Suppl 5): S487-S490, 2021 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-34100804

RESUMO

ABSTRACT: Adipose fat grafting (AFG) is a popular technique used to add volume in the face, breasts, and other tissue deficient areas of the body. In terms of scar release, not only has fat provided additional soft tissue coverage but also the relief of pain in scars in those patients suffering from disease processes, such as complex regional pain syndrome with steroid-induced atrophy, burn scars, morphea, and lupus. The purpose of this article is to demonstrate the senior author's technique and outcomes of using AFG in the face and body for treating volume deficiency, atrophic scarring, and deformities.A retrospective chart review of 127 AFG procedures of the face and body from September 2006 to September 2019 was performed. Of these, 14 patients had scar releases performed with fat grafting of areas of scar contracture. Fat was harvested from the abdomen, thighs, and flanks using Toomey syringes or an enclosed power-assisted system with 3.7- or 3.0-mm cannulas. Grafting in small areas, such as the face, was performed with the 0.9-mm blunt cannula.The majority of AFG was completed in the face (45%), followed by breasts (22%), and scar contracture (16%). The mean volume of fat grafted in procedures involving the breasts, buttocks, and face was 102, 182, and 21 mL, respectively. For scar contracture, the mean volume was 38 mL and for deformations, 27 mL. Sixteen percent of the cohort required at least 1 additional AFG procedure to achieve satisfactory results. There were no major complications, such as skin loss, vascular injury, embolization, or blindness. Minor complications, such as erythema, edema, and hematoma at the fat harvest or graft site, did occur and were managed with local measures.Autologous fat grafting has consistently resulted in volume correction. In addition, in patients with autoimmune disorders, burn scars, and retracted scars, not only has there been volume correction but also decreased pain in the area of treatment. In our series of patients, we described our technique of AFG for the face, body, and scar contracture. Our results demonstrate that AFG remains an inexpensive, safe, and effective treatment option to achieve volume.


Assuntos
Cicatriz , Contratura , Tecido Adiposo , Mama/patologia , Cicatriz/etiologia , Cicatriz/patologia , Cicatriz/cirurgia , Contratura/etiologia , Contratura/cirurgia , Humanos , Estudos Retrospectivos , Transplante Autólogo
10.
Medicine (Baltimore) ; 100(25): e26262, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160389

RESUMO

BACKGROUND: Shear wave elastography (SWE) is a new ultrasonic elastography technique for evaluating the hardness of living tissue by measuring the propagation velocity of shear wave in tissue, which is characterized by real-time, non-invasive and quantitative. The SWE technique can be used to diagnose the lesions of different tissues and organs, and the quantitative measurement of SWE is considered as more objective information about breast masses. Superb microvascular imaging (SMI) is a new noninvasive Doppler ultrasound imaging method, which can display blood flow information with high spatial resolution and high frame rate, while keeping the minimum low-speed blood flow components. Therefore, SMI can diagnose diseases closely related to angiogenesis at a relatively early stage. However, the results of these studies have been contradictory. The present meta-analysis aimed at determining the accuracy of SWE combined with SMI in the differential diagnosis between benign and malignant breast lesions. METHODS: We will search PubMed, Web of Science, Cochrane Library, and Chinese biomedical databases from their inceptions to the April 18, 2021, without language restrictions. Two authors will independently carry out searching literature records, scanning titles and abstracts, full texts, collecting data, and assessing risk of bias. Review Manager 5.2 and Stata14. 0 software will be used for data analysis. RESULTS: This systematic review will determine the accuracy of shear wave elastography combined with superb microvascular imaging in the differential diagnosis between benign and malignant breast tumors. CONCLUSION: Its findings will provide helpful evidence for the accuracy of shear wave elastography combined with superb microvascular imaging in the differential diagnosis between benign and malignant breast tumors. SYSTEMATIC REVIEW REGISTRATION: INPLASY202150075.


Assuntos
Neoplasias da Mama/diagnóstico , Técnicas de Imagem por Elasticidade/métodos , Neovascularização Patológica/diagnóstico , Ultrassonografia Doppler/métodos , Ultrassonografia Mamária/métodos , Mama/irrigação sanguínea , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Estudos de Casos e Controles , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Humanos , Metanálise como Assunto , Microvasos/diagnóstico por imagem , Imagem Multimodal/métodos , Neovascularização Patológica/patologia , Valor Preditivo dos Testes , Revisões Sistemáticas como Assunto
11.
Medicine (Baltimore) ; 100(25): e26469, 2021 Jun 25.
Artigo em Inglês | MEDLINE | ID: mdl-34160454

RESUMO

RATIONALE: With the absence of ophthalmopathy, thyroid dermopathy especially lesions at atypical locations is a very rare presentation. We herein report an original case of bilateral breast myxedema caused by Grave's disease. PATIENT CONCERNS: A 21-year-old unmarried woman presented with a 4-month history of Grave's disease and a 1-month history of progressive bilateral breast enlargement. She had symmetrical bilateral breast enlargement with redness and nonpitting thickening of the skin, diffusely enlarged thyroid glands, and no exophthalmos. DIAGNOSIS: Ultrasonography, magnetic resonance imaging scan, and skin biopsy confirmed the diagnosis of bilateral breast myxedema. INTERVENTIONS: The patient was treated with multipoint subcutaneous injections of triamcinolone acetonide in each breast every month. OUTCOMES: The bilateral breast returned approximately to its normal size after therapy for 6 months. CONCLUSIONS: Our case illustrates that multipoint subcutaneous injection of glucocorticoids is beneficial for bilateral breast myxedema.


Assuntos
Doenças Mamárias/tratamento farmacológico , Glucocorticoides/administração & dosagem , Doença de Graves/complicações , Mixedema/tratamento farmacológico , Biópsia , Mama/diagnóstico por imagem , Mama/patologia , Doenças Mamárias/diagnóstico , Doenças Mamárias/etiologia , Doenças Mamárias/patologia , Feminino , Humanos , Injeções Subcutâneas , Imageamento por Ressonância Magnética , Mixedema/diagnóstico , Mixedema/etiologia , Mixedema/patologia , Pele/diagnóstico por imagem , Pele/patologia , Resultado do Tratamento , Triancinolona Acetonida/administração & dosagem , Ultrassonografia Mamária , Adulto Jovem
12.
Int J Mol Sci ; 22(10)2021 May 17.
Artigo em Inglês | MEDLINE | ID: mdl-34067547

RESUMO

Resveratrol (RSV) is a natural compound that displays several pharmacological properties, including anti-cancer actions. However, its clinical application is limited because of its low solubility and bioavailability. Here, the antiproliferative and anti-inflammatory activity of a series of phenylacetamide RSV derivatives has been evaluated in several cancer cell lines. These derivatives contain a monosubstituted aromatic ring that could mimic the RSV phenolic nucleus and a longer flexible chain that could confer a better stability and bioavailability than RSV. Using MTT assay, we demonstrated that most derivatives exerted antiproliferative effects in almost all of the cancer cell lines tested. Among them, derivative 2, that showed greater bioavailability than RSV, was the most active, particularly against estrogen receptor positive (ER+) MCF7 and estrogen receptor negative (ER-) MDA-MB231 breast cancer cell lines. Moreover, we demonstrated that these derivatives, particularly derivative 2, were able to inhibit NO and ROS synthesis and PGE2 secretion in lipopolysaccharide (LPS)-activated U937 human monocytic cells (derived from a histiocytoma). In order to define the molecular mechanisms underlying the antiproliferative effects of derivative 2, we found that it determined cell cycle arrest at the G1 phase, modified the expression of cell cycle regulatory proteins, and ultimately triggered apoptotic cell death in both breast cancer cell lines. Taken together, these results highlight the studied RSV derivatives, particularly derivative 2, as promising tools for the development of new and more bioavailable derivatives useful in the treatment of breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Resveratrol/farmacologia , Apoptose/efeitos dos fármacos , Disponibilidade Biológica , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Ciclo Celular/efeitos dos fármacos , Pontos de Checagem do Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/metabolismo , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Fase G1/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Células MCF-7 , Resveratrol/análogos & derivados
13.
Lab Invest ; 101(8): 1048-1059, 2021 08.
Artigo em Inglês | MEDLINE | ID: mdl-34031538

RESUMO

Breast cancer, the most common malignancy among women, is closely associated with mutations in the tumor suppressor gene BRCA. DSS1, a component of the TRanscription-EXport-2 (TREX-2) complex involved in transcription and mRNA nuclear export, stabilizes BRCA2 expression. DSS1 is also related to poor prognosis in patients with breast cancer owing to the induction of chemoresistance. Recently, BRCA2 was shown to be associated with the TREX-2 component PCID2, which prevents DNA:RNA hybrid R-loop formation and transcription-coupled DNA damage. This study aimed to elucidate the involvement of these TREX-2 components and BRCA2 in the chemosensitivity of breast carcinomas. Our results showed that compared with that in normal breast tissues, DSS1 expression was upregulated in human breast carcinoma, whereas PCID2 expression was comparable between normal and malignant tissues. We then compared patient survival time among groups divided by high or low expressions of DSS1, BRCA2, and PCID2. Increased DSS1 expression was significantly correlated with poor prognosis in recurrence-free survival time, whereas no differences were detected in the high and low BRCA2 and PCID2 expression groups. We performed in vitro analyses, including propidium iodide nuclear staining, single-cell gel electrophoresis, and clonogenic survival assays, using breast carcinoma cell lines. The results confirmed that DSS1 depletion significantly increased chemosensitivity, whereas overexpression conferred chemoresistance to breast cancer cell lines; however, BRCA2 expression did not affect chemosensitivity. Similar to DSS1, PCID2 expression was also inversely correlated with chemosensitivity. These results strongly suggest that DSS1 and PCID2 depletion is closely associated with increased chemosensitivity via BRCA2-independent DNA damage. Together with the finding that DSS1 is not highly expressed in normal breast tissues, these results demonstrate that DSS1 depletion confers a druggable trait and may contribute to the development of novel chemotherapeutic strategies to treat DSS1-depleted breast carcinomas independent of BRCA2 mutations.


Assuntos
Proteína BRCA2/genética , Neoplasias da Mama/genética , Dano ao DNA/genética , Resistencia a Medicamentos Antineoplásicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Feminino , Humanos , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Complexo de Endopeptidases do Proteassoma/genética , Complexo de Endopeptidases do Proteassoma/metabolismo
14.
Breast Cancer Res Treat ; 188(3): 649-659, 2021 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-33934277

RESUMO

PURPOSE: Diagnosis of breast preneoplastic and neoplastic lesions is difficult due to their similar morphology in breast biopsy specimens. To diagnose these lesions, pathologists perform immunohistochemical analysis and consult with expert breast pathologists. These additional examinations are time-consuming and expensive. Artificial intelligence (AI)-based image analysis has recently improved, and may help in ordinal pathological diagnosis. Here, we showed the significance of machine learning-based image analysis of breast preneoplastic and neoplastic lesions for facilitating high-throughput diagnosis. METHODS: Images were obtained from normal mammary glands, hyperplastic lesions, preneoplastic lesions and neoplastic lesions, such as usual ductal hyperplasia (UDH), columnar cell lesion (CCL), ductal carcinoma in situ (DCIS), and DCIS with comedo necrosis (comedo DCIS) in breast biopsy specimens. The original enhanced convoluted neural network (CNN) system was used for analyzing the pathological images. RESULTS: The AI-based image analysis provided the following area under the curve values (AUC): normal lesion versus DCIS, 0.9902; DCIS versus comedo DCIS, 0.9942; normal lesion versus CCL, 0.9786; and UDH versus DCIS, 1.000. Multiple comparison analysis showed precision and recall scores similar to those of single comparison analysis. Based on the gradient-weighted class activation mapping (Grad-CAM) used to visualize the important regions reflecting the result of CNN analysis, the ratio of stromal tissue in the whole weighted area was significantly higher in UDH and CCL than that in DCIS. CONCLUSIONS: These analyses may provide a more accurate and rapid pathological diagnosis of patients. Moreover, Grad-CAM identifies uncharted important histological characteristics for newer pathological findings and targets of research for understanding diseases.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Inteligência Artificial , Biópsia , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Humanos , Hiperplasia/patologia , Aprendizado de Máquina
15.
J Vis Exp ; (170)2021 04 23.
Artigo em Inglês | MEDLINE | ID: mdl-33970144

RESUMO

Breast cancer (BC) remains a leading cause of death for women. Despite more than $700 million invested in BC research annually, 97% of candidate BC drugs fail clinical trials. Therefore, new models are needed to improve our understanding of the disease. The NIH Microphysiological Systems (MPS) program was developed to improve the clinical translation of basic science discoveries and promising new therapeutic strategies. Here we present a method for generating MPS for breast cancers (BC-MPS). This model adapts a previously described approach of culturing primary human white adipose tissue (WAT) by sandwiching WAT between adipose-derived stem cell sheets (ASC)s. Novel aspects of our BC-MPS include seeding BC cells into non-diseased human breast tissue (HBT) containing native extracellular matrix, mature adipocytes, resident fibroblasts, and immune cells; and sandwiching the BC-HBT admixture between HBT-derived ASC sheets. The resulting BC-MPS is stable in culture ex vivo for at least 14 days. This model system contains multiple elements of the microenvironment that influence BC including adipocytes, stromal cells, immune cells, and the extracellular matrix. Thus BC-MPS can be used to study the interactions between BC and its microenvironment. We demonstrate the advantages of our BC-MPS by studying two BC behaviors known to influence cancer progression and metastasis: 1) BC motility and 2) BC-HBT metabolic crosstalk. While BC motility has previously been demonstrated using intravital imaging, BC-MPS allows for high-resolution time-lapse imaging using fluorescence microscopy over several days. Furthermore, while metabolic crosstalk was previously demonstrated using BC cells and murine pre-adipocytes differentiated into immature adipocytes, our BC-MPS model is the first system to demonstrate this crosstalk between primary human mammary adipocytes and BC cells in vitro.


Assuntos
Neoplasias da Mama/fisiopatologia , Mama/patologia , Diferenciação Celular , Feminino , Humanos , Microambiente Tumoral
16.
Nat Commun ; 12(1): 3140, 2021 05 25.
Artigo em Inglês | MEDLINE | ID: mdl-34035258

RESUMO

INPP4B suppresses PI3K/AKT signaling by converting PI(3,4)P2 to PI(3)P and INPP4B inactivation is common in triple-negative breast cancer. Paradoxically, INPP4B is also a reported oncogene in other cancers. How these opposing INPP4B roles relate to PI3K regulation is unclear. We report PIK3CA-mutant ER+ breast cancers exhibit increased INPP4B mRNA and protein expression and INPP4B increased the proliferation and tumor growth of PIK3CA-mutant ER+ breast cancer cells, despite suppression of AKT signaling. We used integrated proteomics, transcriptomics and imaging to demonstrate INPP4B localized to late endosomes via interaction with Rab7, which increased endosomal PI3Kα-dependent PI(3,4)P2 to PI(3)P conversion, late endosome/lysosome number and cargo trafficking, resulting in enhanced GSK3ß lysosomal degradation and activation of Wnt/ß-catenin signaling. Mechanistically, Wnt inhibition or depletion of the PI(3)P-effector, Hrs, reduced INPP4B-mediated cell proliferation and tumor growth. Therefore, INPP4B facilitates PI3Kα crosstalk with Wnt signaling in ER+ breast cancer via PI(3,4)P2 to PI(3)P conversion on late endosomes, suggesting these tumors may be targeted with combined PI3K and Wnt/ß-catenin therapies.


Assuntos
Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Animais , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Mama/patologia , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Linhagem Celular Tumoral , Proliferação de Células/efeitos dos fármacos , Classe I de Fosfatidilinositol 3-Quinases/genética , Endossomos/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Lisossomos/metabolismo , Camundongos , Mutação , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolases/antagonistas & inibidores , Proteólise/efeitos dos fármacos , Proteômica , Tiazóis/farmacologia , Tiazóis/uso terapêutico , Análise Serial de Tecidos , Via de Sinalização Wnt/efeitos dos fármacos , Ensaios Antitumorais Modelo de Xenoenxerto , Proteínas rab de Ligação ao GTP/metabolismo
17.
Medicine (Baltimore) ; 100(18): e25545, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33950928

RESUMO

BACKGROUND: Breast cancer is a common malignant tumor in women. In recent years, its incidence is increasing year by year, and its morbidity and mortality rank the first place among female malignant tumors. Some key enzymes and intermediates in glycolysis are closely related to tumor development. Pyruvate kinase M2 (PKM2) is an important rate-limiting enzyme in glycolysis pathway. Meanwhile, it is highly expressed in proliferative cells, especially in tumor cells, and plays an important role in the formation of Warburg effect and tumorigenesis. Previous studies have explored the effects of PKM2 expression on the prognosis and clinical significance of breast cancer patients, while the results are contradictory and uncertain. This study uses controversial data for meta-analysis to accurately evaluate the problem. We collected relevant Oncomine and The Cancer Genome Atlas (TCGA) data to further verify the results. Through bioinformatics analysis, the mechanism and related pathways of PKM2 in breast cancer are explored. METHODS: We searched Wanfang, Chinese Biomedical Literature Database, Chinese National Knowledge Infrastructure, the Chongqing VIP Chinese Science and Technology Periodical Database, PubMed, Embase, and Web of Science databases from inception to March 2021. The language restrictions are Chinese and English. The published literatures on PKM2 expression and prognosis or clinicopathological characteristics of breast cancer patients were statistically analyzed. Combined hazard ratios (HRs), odds ratios (ORs), and 95% confidence intervals (95% CIs) were used to evaluate the effects of PKM2 on the prognosis and clinicopathological features of breast cancer. Stata 14.0 software was applied for meta-analysis. Oncomine and TCGA databases were used to meta-analyze the differences of PKM2 mRNA expression between breast cancer and normal breast tissues. The expression of PKM2 protein was verified by Human Protein Atlas (HPA) database. The relationship between the gene and the survival of breast cancer patients was analyzed by Gene Expression Profiling Interactive Analysis (GEPIA). The relationship between PKM2 gene and clinicopathological characteristics was analyzed by using LinkedOmics, and the Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment pathway analysis was performed by using Metascape. Protein-protein interaction (PPI) network was constructed by String website. RESULTS: The results of this meta-analysis will be submitted to a peer-reviewed journal for publication. CONCLUSION: This study provides high-quality medical evidence for the correlation between the expression of PKM2 and the prognosis and clinicopathological features of breast cancer. Through bioinformatics analysis, this study further deepens the understanding of the mechanism and related pathways of PKM2 in breast cancer. ETHICS AND DISSEMINATION: The private information from individuals will not be published. This systematic review also should not damage participants' rights. Ethical approval is not available. The results may be published in a peer-reviewed journal or disseminated in relevant conferences. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/W52HB.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/mortalidade , Mama/patologia , Carcinogênese/patologia , Proteínas de Transporte/metabolismo , Proteínas de Membrana/metabolismo , Hormônios Tireóideos/metabolismo , Biomarcadores Tumorais/análise , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/patologia , Proteínas de Transporte/análise , Biologia Computacional , Intervalo Livre de Doença , Feminino , Humanos , Proteínas de Membrana/análise , Metanálise como Assunto , Prognóstico , Medição de Risco/métodos , Hormônios Tireóideos/análise , Efeito Warburg em Oncologia
18.
Medicine (Baltimore) ; 100(18): e25880, 2021 May 07.
Artigo em Inglês | MEDLINE | ID: mdl-33951002

RESUMO

ABSTRACT: Whether breast-conserving therapy (BCT) should be chosen as a local treatment for young women with early-stage breast cancer is controversial. This study compared the survival benefits of BCT or mastectomy in young women under 40 with early-stage breast cancer and further explored age-stratified outcomes. This study investigated whether there is a survival benefit when young women undergo BCT compared with mastectomy.The characteristics and prognosis of white women under 40 with stage I-II breast cancer from 1988 to 2016 were analyzed using the Surveillance, Epidemiology, and End Results (SEER) database. These women were either treated with BCT or mastectomy. The log-rank test of the Kaplan-Meier survival curve and Cox proportional risk regression model were used to analyze the data and survival. The analysis was stratified by age (18-35 and 36-40 years).A total of 23,810 breast cancer patients were included, of whom 44.9% received BCT and 55.1% underwent mastectomy, with a median follow-up of 116 months. Patients undergoing mastectomy had a higher tumor burden and younger age. By the end of the 20th century, the proportion of BCT had grown from nearly 35% to approximately 60%, and then gradually fell to 35% into the 21st century. Compared with the mastectomy group, the BCT group had improved breast cancer-specific survival (BCSS) (hazard ratio [HR] 0.917; 95% CI, 0.846-0.995, P = .037) and overall survival (OS) (HR 0.925; 95% CI, 0.859-0.997, P = .041). In stratified analysis according to the different ages, the survival benefit of BCT was more pronounced in the slightly older (36-40 years) group while there was no significant survival difference in the younger group (18-35 years).In young women with early-stage breast cancer, BCT showed survival benefits that were at least no worse than mastectomy, and these benefits were even better in the 36 to 40 years age group. Young age may not be a contraindication for BCT.


Assuntos
Neoplasias da Mama/cirurgia , Tomada de Decisão Clínica , Mastectomia Segmentar/estatística & dados numéricos , Mastectomia/estatística & dados numéricos , Adolescente , Adulto , Fatores Etários , Mama/patologia , Mama/cirurgia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Contraindicações de Procedimentos , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Mastectomia Segmentar/efeitos adversos , Estadiamento de Neoplasias , Prognóstico , Medição de Risco/estatística & dados numéricos , Programa de SEER/estatística & dados numéricos , Resultado do Tratamento , Carga Tumoral , Adulto Jovem
19.
Am J Surg ; 221(6): 1167-1171, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33810833

RESUMO

BACKGROUND: Surgical decisions for ductal carcinoma in situ (DCIS) are based on lesion sizes. This study aims to determine the accuracy of pre-operative imaging in estimating the size of DCIS. METHODS: This was a retrospective review of clinicopathologic data of patients treated for DCIS with breast conserving surgery (BCS) between 2012 and 2018. Mammographic and sonographic lesion sizes were compared with final pathology sizes. RESULTS: For the 152 lesions visible on mammography, mean size on imaging was significantly smaller when compared to final pathology (2.3 vs. 3.6 cm, p < 0.001). The mean difference of 1.3 cm was a significant underestimation with a correlation coefficient of 0.367 (p < 0.001). For 48 sonographically visible lesions, the radiologic size was significantly smaller than pathologic size (1.7 vs. 4.1 cm, p < 0.001), but the degree of underestimation was not significantly correlated (p = 0.379). CONCLUSION: DCIS size was significantly underestimated by imaging. This must be taken into consideration during surgical planning.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Carcinoma Intraductal não Infiltrante/diagnóstico por imagem , Mamografia , Ultrassonografia Mamária , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia por Agulha , Mama/diagnóstico por imagem , Mama/patologia , Neoplasias da Mama/patologia , Carcinoma Intraductal não Infiltrante/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos
20.
Radiology ; 300(1): 46-54, 2021 07.
Artigo em Inglês | MEDLINE | ID: mdl-33904772

RESUMO

Background In the post-American College of Surgeons Oncology Group Z0011 trial era, radiologists have increasingly focused on excluding high-level or advanced axillary lymph node metastasis (ALNM) by using an additional MRI scan positioned higher than lower axillae; however, the value of these additional scans remains undetermined. Purpose To evaluate whether a standard MRI protocol is sufficient to exclude high-level or advanced ALNM in breast cancer or additional MRI of entire axilla is needed. Materials and Methods This retrospective study evaluated women with invasive breast cancer who underwent breast MRI from April 2015 to December 2016. Some underwent neoadjuvant chemotherapy (NAC) and others underwent upfront surgery. Standard (routine axial scans including the lower axillae) and combined (routine axial scans plus additional scans including the entire axilla) MRI protocols were compared for high-level or advanced ALNM detection. Clinical-pathologic characteristics were analyzed. Uni- and multivariable logistic regression was performed to identify predictors of high-level or advanced ALNM. Results A total of 435 women (mean age ± standard deviation, 52 years ± 11) were evaluated (65 in the NAC group, 370 in the non-NAC group). With the standard MRI protocol, predictors of high-level ALNM were peritumoral edema (odds ratio [OR], 12.3; 95% CI: 3.9, 39.4; P < .001) and positive axilla (OR, 5.9; 95% CI: 2.0, 15.2; P < .001). Only three of 289 women with negative axillae without peritumoral edema had high-level ALNM. Predictors of advanced ALNM were positive axillae (OR, 8.9; 95% CI: 3.7, 21.5; P < .001) and peritumoral edema (OR, 2.8; 95% CI: 1.1, 6.9; P = .03). Only six of 310 women who had negative axillae without peritumoral edema had advanced ALNM. Conclusion The performance of standard MRI was satisfactory in excluding high-level and advanced axillary lymph node metastasis in most patients with breast cancer. However, the presence of peritumoral edema or positive axillae in the MRI findings emphasizes the benefits of a combined MRI protocol. © RSNA, 2021 Online supplemental material is available for this article. See also the editorial by Abe in this issue.


Assuntos
Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Metástase Linfática/diagnóstico por imagem , Metástase Linfática/patologia , Imageamento por Ressonância Magnética/métodos , Adulto , Idoso , Idoso de 80 Anos ou mais , Axila , Mama/diagnóstico por imagem , Mama/patologia , Feminino , Humanos , Linfonodos/diagnóstico por imagem , Linfonodos/patologia , Pessoa de Meia-Idade , Invasividade Neoplásica , Reprodutibilidade dos Testes , Estudos Retrospectivos
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