Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 3.552
Filtrar
1.
Nat Commun ; 13(1): 3399, 2022 Jun 13.
Artigo em Inglês | MEDLINE | ID: mdl-35697697

RESUMO

Ductal carcinoma in situ (DCIS) is considered a non-invasive precursor to breast cancer, and although associated with an increased risk of developing invasive disease, many women with DCIS will never progress beyond their in situ diagnosis. The path from normal duct to invasive ductal carcinoma (IDC) is not well understood, and efforts to do so are hampered by the substantial heterogeneity that exists between patients, and even within patients. Here we show gene expression analysis from > 2,000 individually micro-dissected ductal lesions representing 145 patients. Combining all samples into one continuous trajectory we show there is a progressive loss in basal layer integrity heading towards IDC, coupled with two epithelial to mesenchymal transitions, one early and a second coinciding with the convergence of DCIS and IDC expression profiles. We identify early processes and potential biomarkers, including CAMK2N1, MNX1, ADCY5, HOXC11 and ANKRD22, whose reduced expression is associated with the progression of DCIS to invasive breast cancer.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Biomarcadores , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/patologia , Progressão da Doença , Feminino , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Humanos , Fatores de Transcrição/genética , Transcriptoma
2.
Neoplasia ; 28: 100791, 2022 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-35405500

RESUMO

With over 60,000 cases diagnosed annually in the US, ductal carcinoma in situ (DCIS) is the most prevalent form of early-stage breast cancer. Because many DCIS cases never progress to invasive ductal carcinomas (IDC), overtreatment remains a significant problem. Up to 20% patients experience disease recurrence, indicating that standard treatments do not effectively treat DCIS for a subset of patients. By understanding the mechanisms of DCIS progression, we can develop new treatment strategies better tailored to patients. The chemokine CCL2 and its receptor CCR2 are known to regulate macrophage recruitment during inflammation and cancer progression. Recent studies indicate that increased CCL2/CCR2 signaling in breast epithelial cells enhance formation of IDC. Here, we characterized the molecular mechanisms important for CCL2/CCR2-mediated DCIS progression. Phospho-protein array profiling revealed that CCL2 stimulated phosphorylation of MET receptor tyrosine kinases in breast cancer cells. Co-immunoprecipitation and proximity ligation assays demonstrated that CCL2-induced MET activity depended on interactions with CCR2 and SRC. Extracellular flux analysis and biochemical assays revealed that CCL2/CCR2 signaling in breast cancer cells enhanced glycolytic enzyme expression and activity. CRISPR knockout and pharmacologic inhibition of MET revealed that CCL2/CCR2-induced breast cancer cell proliferation, survival, migration and glycolysis through MET-dependent mechanisms. In animals, MET inhibitors blocked CCR2-mediated DCIS progression and metabolism. CCR2 and MET were significantly co-expressed in patient DCIS and IDC tissues. In summary, MET receptor activity is an important mechanism for CCL2/CCR2-mediated progression and metabolism of early-stage breast cancer, with important clinical implications.


Assuntos
Neoplasias da Mama , Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Quimiocina CCL2 , Proteínas Proto-Oncogênicas c-met , Receptores CCR2 , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Linhagem Celular Tumoral , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Progressão da Doença , Feminino , Humanos , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/patologia , Proteínas Proto-Oncogênicas c-met/metabolismo , Receptores CCR2/metabolismo
3.
Sci Rep ; 12(1): 2120, 2022 02 08.
Artigo em Inglês | MEDLINE | ID: mdl-35136078

RESUMO

Cytochrome c (Cyt c) is a key protein that is needed to maintain life (respiration) and cell death (apoptosis). The dual-function of Cyt c comes from its capability to act as mitochondrial redox carrier that transfers electrons between the membrane-embedded complexes III and IV and to serve as a cytoplasmic apoptosis-triggering agent, activating the caspase cascade. However, the precise roles of Cyt c in mitochondria, cytoplasm and extracellular matrix under normal and pathological conditions are not completely understood. To date, no pathway of Cyt c release that results in caspase activation has been compellingly demonstrated in any invertebrate. The significance of mitochondrial dysfunctionality has not been studied in ductal carcinoma to the best of our knowledge. We used Raman spectroscopy and imaging to monitor changes in the redox state of the mitochondrial cytochromes in ex vivo surgically resected specimens of human breast tissues, and in vitro human breast cells of normal cells (MCF 10A), slightly malignant cells (MCF7) and highly aggressive cells (MDA-MB-231). We showed that Raman imaging provides insight into the biology of human breast ductal cancer. Here we show that proper concentration of monounsaturated fatty acids, saturated fatty acids, cardiolipin and Cyt c is critical in the correct breast ductal functioning and constitutes an important parameter to assess breast epithelial cells integrity and homeostasis. We look inside human breast ducts by Raman imaging answering fundamental questions about location and distribution of various biochemical components inside the lumen, epithelial cells of the duct and the extracellular matrix around the cancer duct during cancer development in situ. Our results show that human breast cancers demonstrate a redox imbalance compared to normal tissue. The reduced cytochrome c is upregulated in all stages of cancers development. The results of the paper shed light on a largely non-investigated issues regarding cytochromes and mitochondrial function in electron transfer chain. We found in histopathologically controlled breast cancer duct that Cyt c, cardiolipin, and palmitic acid are the main components inside the lumen of cancerous duct in situ. The presented results show direct evidence that Cyt c is released to the lumen from the epithelial cells in cancerous duct. In contrast the lumen in normal duct is empty and free of Cyt c. Our results demonstrate how Cyt c is likely to function in cancer development. We anticipate our results to be a starting point for more sophisticated in vitro and in vivo animal models. For example, the correlation between concentration of Cyt c and cancer grade could be tested in various types of cancer. Furthermore, Cyt c is a target of anti-cancer drug development and a well-defined and quantitative Raman based assay for oxidative phosphorylation and apoptosis will be relevant for such developments.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Citocromos c/metabolismo , Mitocôndrias/metabolismo , Análise Espectral Raman , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/etiologia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/etiologia , Feminino , Humanos , Técnicas In Vitro , Células MCF-7 , Oxirredução
4.
PLoS One ; 17(1): e0262709, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35051228

RESUMO

BACKGROUND: We compared the clinicopathological characteristics and survival outcomes of invasive lobular carcinoma (ILC) cases with those of invasive ductal carcinoma (IDC) cases in various hormone receptor expression subgroups. METHODS: We compared clinicopathological characteristics, overall survival (OS), and breast cancer-specific survival (BCSS) between patients with IDC (n = 95,486) and ILC (n = 3,023). In addition, we analyzed the effects of different hormone receptor expression subgroups on survival. RESULTS: The ILC group had more instances of advanced stage and hormonal receptor positivity than did the IDC group (p < 0.001), but the IDC group had higher histological grade and nuclear grade, as well as higher frequency of human epidermal growth factor receptor 2 and Ki67 expression than did the ILC group (p < 0.001). The OS and BCSS were not significantly different between the IDC and ILC groups. The 5-year OS of the IDC group was 88.8%, while that of the ILC group was 90.6% (p = 0.113). The 5-year BCSS of the IDC group was 94.8%, while that of the ILC group was 95.0% (p = 0.552). When analyzing each hormone receptor expression subgroup, there were no significant differences in survival between the IDC and ILC groups. However, the estrogen receptor (ER) negative/progesterone receptor (PR) negative subgroup showed differences in survival between the IDC and ILC groups. Moreover, the hazard ratio of ILC in the ER negative/PR negative subgroup was 1.345 (95% confidence interval: 1.012-1.788; p = 0.041). CONCLUSIONS: Hormone receptor expression should be considered when determining prognosis and treatment regimen for IDC and ILC. Researchers should further study the ER negative/PR negative population to identify treatment and prognostic models that will facilitate the development of individualized therapy for these patients, which is needed for good outcomes.


Assuntos
Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/mortalidade , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Mama/metabolismo , Mama/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Prognóstico , República da Coreia/epidemiologia , Análise de Sobrevida , Taxa de Sobrevida
5.
Ann Surg Oncol ; 29(4): 2263-2272, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34994896

RESUMO

BACKGROUND: Omission of sentinel lymph node biopsy (SLNB) in older women with clinically node-negative, hormone receptor-positive (HR+) early-stage breast cancer undergoing lumpectomy is accepted, given established low rates of regional recurrence. The safety of omitting SLNB in women undergoing mastectomy is unknown and may differ depending on extent of breast disease and variation in radiotherapy use. PATIENTS AND METHODS: From 2006 to 2018, 123 cTis and 328 cT1-2 HR+/HER2- tumors from 410 women aged ≥ 70 years who underwent mastectomy and SLNB were included (41 bilateral cases). The rate of nodal positivity and effect of nodal positivity on adjuvant therapy use were examined. RESULTS: Median age was 74 years; 21% of patients had positive sentinel lymph nodes, 7% had micrometastases, and 14% had macrometastases. Of cases of cTis tumors, 31% were upstaged to invasive carcinoma; 1% had macrometastases. Fewer cases of cT1 than cT2 tumors had macrometastases [13% (26/200) versus 29% (37/128); p < 0.001]. Eight percent of patients with pT1 tumors (18/228) and 27% of patients with pT2 tumors (30/113) received chemotherapy. Most patients with pT1, pN1 disease (78%; 25/32) did not receive chemotherapy. Rates of locoregional recurrence were similar between patients with cT1 or cT2 tumors with and without nodal metastases (median follow-up, 4.5 years). CONCLUSIONS: Women aged ≥ 70 years with cTis and cT1N0 HR+/HER2- tumors who underwent mastectomy had low rates of nodal positivity, similar to rates reported for lumpectomy. Given this and the RxPONDER results, omission of SLNB may be considered, as findings are unlikely to alter adjuvant therapy recommendations.


Assuntos
Carcinoma Ductal de Mama , Carcinoma Intraductal não Infiltrante , Mastectomia , Biópsia de Linfonodo Sentinela , Idoso , Axila/patologia , Axila/cirurgia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Intraductal não Infiltrante/metabolismo , Carcinoma Intraductal não Infiltrante/patologia , Carcinoma Intraductal não Infiltrante/cirurgia , Feminino , Humanos , Mastectomia/métodos , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/cirurgia , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese
6.
Surgery ; 171(3): 666-672, 2022 03.
Artigo em Inglês | MEDLINE | ID: mdl-34862071

RESUMO

BACKGROUND: During the COVID-19 pandemic, guidelines recommended that breast cancer centers delay estrogen receptor-positive breast cancer surgeries with neoadjuvant endocrine therapy. We aimed to evaluate pathologic upstaging of breast cancer patients affected by these guidelines. METHODS: Female patients with stage I/II breast cancer receiving neoadjuvant endocrine therapy were prospectively identified and were matched to a historical cohort of stage I/II estrogen receptor-positive breast cancer patients treated with upfront surgery ≤35 days. Primary outcomes were pathologic T and N upstaging versus clinical staging. RESULTS: After matching, 28 neoadjuvant endocrine therapy and 48 control patients remained. Median age in each group was 65 (P = .68). Most patients (78.6% and 79.2%) had invasive ductal carcinoma with a clinical tumor size of 0.9 cm vs 1.7 cm (P = .056). Time to surgery was 68 days in the neoadjuvant endocrine therapy group and 26.5 days in the control (P < .001). A total of 23 neoadjuvant endocrine therapy patients (82.1%) had the same or lower pT-stage compared with 31 (64.5%) control patients (P = .115). Only 3 (10.7%) neoadjuvant endocrine therapy patients had increased pN-stage vs 14 (29.2%) control patients (P = .063). CONCLUSION: Despite 2.5-times longer delays, patients with early-stage estrogen receptor-positive breast cancer receiving neoadjuvant endocrine therapy did not experience pathologic upstaging during the COVID-19 pandemic. These findings may support the use of neoadjuvant endocrine therapy in similar patients if delays to surgery are projected.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/cirurgia , COVID-19 , Carcinoma Ductal de Mama/cirurgia , Tempo para o Tratamento/estatística & dados numéricos , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Estudos de Casos e Controles , Feminino , Humanos , Mastectomia/estatística & dados numéricos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estudos Prospectivos , Receptores de Estrogênio/metabolismo
7.
Dig Dis Sci ; 67(2): 437-444, 2022 02.
Artigo em Inglês | MEDLINE | ID: mdl-34731362

RESUMO

Multiple primary malignant neoplasms (MPMN) represent the occurrence of a second malignancy in the same patient within 6 months after the detection of first primary (synchronous) tumor, or > 6 months after primary detection (metachronous). We present a case of a patient treated for carcinoma of the breast who developed a metachronous primary malignancy in the colorectal tract. These tumors were histologically different with distinct immune-histochemical parameters. The association between breast and colon cancer is well documented in the literature with several studies reporting the coexistence of common extrinsic and genetic predisposing factors. Although rare, MPMN are becoming more common due to the increased number of elderly cancer survivors, improved diagnosis and enhanced awareness. The association between colorectal and breast cancer should not be dismissed merely as metastasis since there is good precedent for the co-occurrence of these primary tumors.


Assuntos
Adenocarcinoma/diagnóstico por imagem , Neoplasias da Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/diagnóstico por imagem , Neoplasias Colorretais/diagnóstico por imagem , Neoplasias Primárias Múltiplas/diagnóstico por imagem , Adenocarcinoma/patologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Neoplasias Colorretais/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Neoplasias Primárias Múltiplas/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
8.
Biochem J ; 479(1): 23-38, 2022 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-34881777

RESUMO

LASP-1 was identified as a protein following mass spectrometric analysis of phosphoproteins consequent to signaling by ErbB2 in SKOV-3 cells. It has been previously identified as an oncogene and is located on chromosomal arm 17q 0.76 Mb centromeric to ErbB2. It is expressed in serous ovarian cancer cell lines as a 40 kDa protein. In SKOV-3 cells, it was phosphorylated and was inhibited by Lapatinib and CP7274714. LASP-1 co-immunoprecipitated with ErbB2 in SKOV-3 cells, suggesting a direct interaction. This interaction and phosphorylation were independent of the kinase activity of ErbB2. Moreover, the binding of LASP-1 to ErbB2 was independent of the tyrosine phosphorylation of LASP-1. LASP-1 was neither expressed on the surface epithelium of the normal ovary nor in the fallopian tube. It was expressed in 28% of ovarian tumours (n = 101) that did not significantly correlate with other clinical factors. In tumours from patients with invasive ductal carcinoma of the breast who had ErbB2 amplification (3+), LASP-1 was expressed in 3/20 (P < 0.001). Analysis of the expression of an independent dataset of ovarian and breast tumours from TCGA showed the significant co-occurrence of ErbB2 and LASP-1 (P < 0.01). These results suggest that LASP-1 and ErbB2 interaction could be important in the pathogenesis of ovarian cancer.


Assuntos
Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Carcinoma Epitelial do Ovário/metabolismo , Proteínas do Citoesqueleto/metabolismo , Proteínas com Domínio LIM/metabolismo , Neoplasias Ovarianas/metabolismo , Receptor ErbB-2/metabolismo , Transdução de Sinais/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Epitelial do Ovário/patologia , Linhagem Celular Tumoral , Estudos de Coortes , Proteínas do Citoesqueleto/genética , Feminino , Células HEK293 , Humanos , Proteínas com Domínio LIM/genética , Lapatinib/farmacologia , Pessoa de Meia-Idade , Neoplasias Ovarianas/patologia , Fosforilação/efeitos dos fármacos , Fosforilação/genética , Plasmídeos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Receptor ErbB-2/genética , Transdução de Sinais/efeitos dos fármacos , Transfecção
9.
Asian Pac J Cancer Prev ; 22(11): 3493-3498, 2021 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-34837904

RESUMO

BACKGROUND: Abnormal activation of the ß-catenin signaling pathway is involved in various malignancies, including breast carcinoma.Aberrant expression of ß-catenin has been associated with more aggressive behaviors of breast cancer in some previous studies. . In the present study, we intend to evaluate the ß-catenin expression in breast cancer specimens and study its relationship with clinicopathological parameters. MATERIALS AND METHOD: In this cross-sectional study,88 samples diagnosed as invasive ductal breast carcinoma from 2007 to 2017 were evaluated. The slides and paraffin blocks were retrieved from the archive of pathology department. Patients' clinical characteristics and other information were also extracted from medical documents. Sections from related paraffin blocks through the tissue microarray method were provided, and immunohistochemistry staining for ß-catenin was done. Then different patterns of ß-catenin expression and the relationship between different patterns and clinicopathological parameters were investigated. RESULTS: Of the 88 breast cancer samples, 94% were female, and 6% were male. In 70% of the samples, normal membrane expression of ß-catenin was observed. Whereas in 30% of them, aberrant expression of ß-catenin was observed. A close significant relationship was observed between aberrant ß-catenin expression and age over 50 years (p-value: 0.093) and negative HER2 (p-value: 0.07). CONCLUSION: In the present study, a correlation was observed between aberrant ß-catenin expression and age over 50 years in patients and HER2 negativity, although this association was not statistically significant.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , beta Catenina/metabolismo , Adulto , Fatores Etários , Biomarcadores Tumorais/metabolismo , Estudos Transversais , Feminino , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Transdução de Sinais
10.
BMC Cancer ; 21(1): 1151, 2021 Oct 27.
Artigo em Inglês | MEDLINE | ID: mdl-34706697

RESUMO

BACKGROUND: This study aimed to evaluate the potential of metabolic activity of the psoas muscle measured by 18F-fluorodeoxyglucose positron emission tomography-computed tomography to predict treatment outcomes in patients with resectable breast cancer. METHODS: The medical records of 288 patients who had undergone surgical resection for stages I-III invasive ductal carcinoma of the breast between January 2014 and December 2014 in Pusan National University Hospital were reviewed. The standardized uptake values (SUVs) of the bilateral psoas muscle were normalized using the mean SUV of the liver. SUVRmax was calculated as the ratio of the maximum SUV of the average bilateral psoas muscle to the mean SUV of the liver. SUVRmean was calculated as the ratio of the mean SUV of the bilateral psoas muscle to the mean SUV of the liver. RESULTS: Univariate analyses identified a higher T stage, higher N stage, estrogen receptor negativity, progesterone receptor negativity, human epidermal growth factor receptor 2 positivity, triple-negative breast cancer, mastectomy (rather than breast-conserving surgery), SUVRmean > 0.464, and SUVRmax > 0.565 as significant adverse factors for disease-free survival (DFS). Multivariate Cox regression analysis revealed that N3 stage (hazard ratio [HR] = 5.347, P = 0.031) was an independent factor for recurrence. An SUVRmax > 0.565 (HR = 4.987, P = 0.050) seemed to have a correlation with shorter DFS. CONCLUSIONS: A higher SUVRmax of the psoas muscle, which could be a surrogate marker of insulin resistance, showed strong potential as an independent prognostic factor for recurrence in patients with resectable breast cancer.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Fluordesoxiglucose F18/farmacocinética , Resistência à Insulina , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Músculos Psoas/metabolismo , Compostos Radiofarmacêuticos/farmacocinética , Adulto , Idoso , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/diagnóstico por imagem , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Estudos Transversais , Feminino , Humanos , Fígado/metabolismo , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Cuidados Pré-Operatórios , Prognóstico , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Sensibilidade e Especificidade , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas
11.
Sci Rep ; 11(1): 21159, 2021 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-34707101

RESUMO

Using chip array assays, we identified differentially expressed genes via a comparison between luminal A breast cancer subtype and normal mammary ductal cells from healthy donors. In silico analysis confirmed by western blot and immunohistochemistry revealed that C-JUN and C-FOS transcription factors are activated in luminal A patients as potential upstream regulators of these differentially expressed genes. Using a chip-on-chip assay, we identified potential C-JUN and C-FOS targets. Among these genes, the NRIP1 gene was revealed to be targeted by C-JUN and C-FOS. This was confirmed after identification and validation with transfection assays specific binding of C-JUN and C-FOS at consensus binding sites. NRIP1 is not only upregulated in luminal A patients and cell lines but also regulates breast cancer-related genes, including PR, ESR1 and CCND1. These results were confirmed by NRIP1 siRNA knockdown and chip array assays, thus highlighting the putative role of NRIP1 in PGR, ESR1 and CCND1 transcriptional regulation and suggesting that NRIP1 could play an important role in breast cancer ductal cell initiation.


Assuntos
Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Regulação Neoplásica da Expressão Gênica , Proteína 1 de Interação com Receptor Nuclear/metabolismo , Adulto , Idoso , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , Ciclina D1/genética , Ciclina D1/metabolismo , Receptor alfa de Estrogênio/genética , Receptor alfa de Estrogênio/metabolismo , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Células MCF-7 , Pessoa de Meia-Idade , Proteínas Nucleares/genética , Proteínas Nucleares/metabolismo , Proteína 1 de Interação com Receptor Nuclear/genética , Proteínas Proto-Oncogênicas c-fos/metabolismo , Transcriptoma
12.
Pathol Res Pract ; 227: 153645, 2021 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-34678601

RESUMO

Breast cancer is the most common form of cancer in women around the world. The molecular mechanisms of this heterogeneous disease have been extensively investigated; but yet; It requires a lot of sensitive and specific markers for prognosis and early detection approaches. Non-protein coding RNAs known as lncRNAs have been reported in tumorigenic involvement so they can be used for therapeutic purposes. In the present study, the expression levels of CCAT1, PDCD4, PDCD4-AS1, and MEG3 LncRNA in adjacent tumor and breast tissue in 88 Iranian patients were evaluated by quantitative real-time PCR. CCAT1 was significantly expressed and PDCD4-AS1 decreased in tumor samples, PDCD4 and PDCD4-AS1 showed a positive correlation with each other, higher levels of PDCD4-AS1 were associated with better survival, tumor samples showed lower levels of PDCD4 in Showed comparisons with normal tissue. Our findings suggest that lncRNAs play an important role in controlling gene expression after transcription of major tumor suppressors or carcinogenic genes, leading to the development of triple-negative breast cancer (TNBC). In conclusion, this study investigated the prognostic role of lncRNA in breast cancer patients.


Assuntos
Proteínas Reguladoras de Apoptose/genética , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Carcinoma Ductal de Mama/genética , RNA Longo não Codificante/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Proteínas Reguladoras de Apoptose/metabolismo , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/metabolismo , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Pessoa de Meia-Idade , RNA Longo não Codificante/metabolismo , Proteínas de Ligação a RNA/metabolismo
13.
J Cancer Res Ther ; 17(4): 1112-1114, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34528573

RESUMO

Human epidermal growth factor receptor 2 (HER-2) is a checkpoint, controlling cell proliferation and differentiation. Trastuzumab, a humanized monoclonal antibody directed against HER-2, is nowadays standard treatment for breast cancer patients whose tumors express HER-2. It is generally well tolerated, with a small number of patients developing mild adverse reactions. Dermatomyositis is a rare adverse event of trastuzumab therapy not well described in the literature. We herein present a case of a patient treated for hormone-sensitive invasive ductal carcinoma, who presented with symptoms of proximal muscle weakness, arthralgias, skin rash, and generalized fatigue. The symptoms started after the sixth cycle of trastuzumab and progressively deteriorated. The patient's medical and family history was unremarkable. Disease progression as a possible cause of dermatomyositis had been ruled out, and laboratory evaluation revealed moderate elevation of serum muscle proteins and acute-phase reactants. Trastuzumab treatment was discontinued, and 3 months later, the patient was free of symptoms without any further intervention.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Dermatomiosite/patologia , Receptor ErbB-2/metabolismo , Trastuzumab/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Dermatomiosite/induzido quimicamente , Feminino , Humanos , Pessoa de Meia-Idade , Prognóstico
14.
Ann Diagn Pathol ; 55: 151814, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34517157

RESUMO

Breast cancer is a heterogeneous disease, and new biomarkers are needed for more accurate classification and prediction of prognosis. The goal of this study is to assess the expression of breast cancer classification genes, to identify new molecular signatures in different intrinsic subtypes of breast cancer and to correlate their expression with different clinical variables. The study included 84 female patients newly diagnosed with non-metastatic breast cancer at the outpatient clinic at the National Cancer Institute, Cairo University, Egypt. Detection of 17 breast cancer classification genes was done using RT-PCR in tumor and normal tissues. Estrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 expression were assessed using IHC assay for intrinsic subtyping. Combined expression of FOXA1 and GATA3 was statistically higher in luminal subtypes in comparison to non-luminal subtypes. In Luminal A subtype; GRB7, EGFR, PTGS2, ID1, and KRT5 were significantly downregulated. FOXA1 and GATA3 were significantly upregulated in luminal B subtype, where EGFR and PTGS2 were significantly downregulated. While ESR1, EGFR, KRT5 and PTGS2 showed significantly low expression in tumor tissue in Her2 enriched subtype, TFF3 was significantly downregulated in triple negative subtype. GATA3 and FOXA1 expression exhibited significant correlation with tumor grade. Furthermore, GATA3, FOXA1, ESR1, and ID1 were also correlated significantly with staging of the tumor. Combined expression of ESR1, FOXA1 and GATA3 represents a molecular signature of luminal subtypes. Long term follow-up is needed to investigate the prognostic effect of breast cancer classification genes found in this study.


Assuntos
Neoplasias da Mama , Receptor alfa de Estrogênio/metabolismo , Fator de Transcrição GATA3/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Adulto , Idoso , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/classificação , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Diagnóstico Diferencial , Feminino , Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico
15.
Anticancer Res ; 41(9): 4619-4627, 2021 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-34475090

RESUMO

BACKGROUND: The real-world outcomes of patients with advanced invasive lobular carcinoma (ILC) of the breast are unclear because of its rarity. PATIENTS AND METHODS: We identified 435 patients with estrogen receptor-positive (ER+), HER2-negative (HER2-) advanced breast cancer treated at our Institute between 2002 and 2019, and analyzed their outcomes retrospectively. RESULTS: We identified 29 patients with advanced ILC. At presentation, they had a lower rate of lung metastasis (p=0.0053) but a higher rate of stomach metastasis (p=0.0379) compared with other patients with advanced breast cancer. Median overall survival did not differ; however, multivariate analyses showed that ILC histopathology was a risk factor for poorer overall survival (hazard ratio=3.43, p=0.0038) in patients with de novo stage IV ER+ HER2- breast cancer. Patients with ILC showed a markedly different patten of subsequent metastasis, such as less in the lung and more in the stomach, leptomeninges, and bone marrow. CONCLUSION: According to our retrospective study, in patients with de novo stage IV ER+ HER2- breast cancer, ILC histopathology was associated with increased risk of death.


Assuntos
Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/mortalidade , Carcinoma Lobular/metabolismo , Carcinoma Lobular/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos , Análise de Sobrevida
16.
Oncology ; 99(12): 780-789, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34535596

RESUMO

INTRODUCTION: Ki67 as a proliferative marker has prognostic and therapeutic relevance in early breast cancer (EBC). However, standard cutoffs for distinguishing low and high Ki67 do not exist. MATERIAL AND METHODS: Data from all patients treated at the University Hospital Ulm for EBC between January 2013 and December 2015 with documented results for internal Ki67 assessment of the primary (n = 917) tumor were retrospectively analyzed evaluating the associations between Ki67 and other clinicopathological factors. RESULTS: 595 (64.9%) patients had a Ki67 <20% and 322 (35.1%) a Ki67 ≥20%. The median Ki67 was 10% (range 1-90%). Median Ki67 values according to the hormone receptor (HR)/ human epidermal growth factor receptor 2 (HER2) subtypes were 10% for HR-positive/HER2 negative (HR+/HER2-) disease (n = 717), 20% for HR+/HER2+ (n = 76), 30% for HR-/HER2+ (n = 45), and 60% for HR-/HER2- (n = 75). 75.2% or 89.3% of all patients with HER2-positive or triple-negative disease had a Ki67 ≥20%, respectively. Using a multivariable logistic regression with Ki67 (<20% vs. ≥20%) as binary dependent variable, younger age, positive nodal status, higher grading, histological nonspecific type carcinoma, negative HR status, and positive HER2 status were shown to be significantly associated with a higher proliferative index (Ki67 ≥20%). CONCLUSION: This analysis described Ki67 in different subtypes in EBC and its association with clinicopathological factors. According to more aggressive tumor biology, the respective subgroups also showed higher median Ki67 levels. However, definition of low and high proliferation index itself is difficult. It is essential to interpret Ki67 indices carefully with regard to the own institutional values and other clinicopathological factors.


Assuntos
Carcinoma Ductal de Mama/metabolismo , Carcinoma Lobular/metabolismo , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/metabolismo , Carcinoma Ductal de Mama/epidemiologia , Carcinoma Ductal de Mama/patologia , Carcinoma Lobular/epidemiologia , Carcinoma Lobular/patologia , Feminino , Alemanha/epidemiologia , Hospitais Universitários , Humanos , Pessoa de Meia-Idade , Gradação de Tumores , Prognóstico , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologia
17.
Sci Rep ; 11(1): 17750, 2021 09 07.
Artigo em Inglês | MEDLINE | ID: mdl-34493772

RESUMO

Lineage tracing in mice indicates that LGR5 is an adult stem cell marker in multiple organs, such as the intestine, stomach, hair follicles, ovary, and mammary glands. Despite many studies exploring the presence of LGR5 cells in human tissues, little is known about its expression profile in either human mammary tissue or pathological lesions. In this study we aim to investigate LGR5 expression in normal, benign, and malignant lesions of the human breast using RNA in situ hybridization. LGR5 expression has not been observed in normal lactiferous ducts and terminal duct lobular units, whereas LGR5-positive cells have been specifically observed in the basal myoepithelium of ducts in the regenerative tissues, ductal carcinoma in situ, and in ducts surrounded by invasive cancer cells. These findings suggest LGR5 marks facultative stem cells that are involved in post injury regeneration instead of homeostatic stem cells. LGR5 positivity was found in 3% (9 of 278 cases) of invasive breast cancers (BC), and it showed positive associations with higher histologic grades (P = 0.001) and T stages (P < 0.001), while having negative correlations with estrogen receptor (P < 0.001) and progesterone receptor (P < 0.001) expression. Remarkably, all LGR5-positive BC, except one, belong to triple-negative BC (TNBC), representing 24% (9 of 38 cases) of all of them. LGR5 histoscores have no correlations with EGFR, CK5/6, Ki-67, or P53 expression. Additionally, no ß-catenin nuclear localization was observed in LGR5-positive BC, indicating that canonical Wnt pathway activation is less likely involved in LGR5 expression in BC. Our results demonstrate that LGR5 expression is induced in regenerative conditions in the myoepithelium of human mammary ducts and that its expression is only observed in TNBC subtype among all invasive BC. Further studies regarding the functional and prognostic impact of LGR5 in TNBC are warranted.


Assuntos
Mama/metabolismo , Células Epiteliais/metabolismo , Proteínas de Neoplasias/biossíntese , Receptores Acoplados a Proteínas G/biossíntese , Neoplasias de Mama Triplo Negativas/metabolismo , Adulto , Idoso , Mama/citologia , Mama/fisiologia , Doenças Mamárias/genética , Doenças Mamárias/metabolismo , Carcinoma/genética , Carcinoma/metabolismo , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Intraductal não Infiltrante/genética , Carcinoma Intraductal não Infiltrante/metabolismo , Feminino , Fibroadenoma/genética , Fibroadenoma/metabolismo , Humanos , Hibridização In Situ , Pessoa de Meia-Idade , Proteínas de Neoplasias/genética , Papiloma Intraductal/genética , Papiloma Intraductal/metabolismo , Tumor Filoide/genética , Tumor Filoide/metabolismo , RNA Mensageiro/biossíntese , RNA Neoplásico/biossíntese , Receptores Acoplados a Proteínas G/genética , Regeneração/genética , Neoplasias de Mama Triplo Negativas/genética
18.
J Surg Oncol ; 124(8): 1224-1234, 2021 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-34416025

RESUMO

BACKGROUND: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer are treated with trastuzumab-based neoadjuvant therapy (NAT); some patients with residual disease post-NAT show loss of HER2 amplification and has been inconsistently associated with oncologic outcomes. METHODS: We queried our multi-institutional cancer registry for women with HER2-positive breast cancer undergoing NAT from 2011 to 2018. Clinicopathologic, treatment-related, and outcomes data were collected. Kaplan-Meier and Cox proportional hazards analysis were used to evaluate oncologic outcomes. RESULTS: A total of 348 patients were identified; 166 (48%) had a pathologic complete response. Of the 182 patients with residual disease, 87 (48%) were HER2-positive, 34 (19%) were HER2-negative, and 61 (33%) were HER2-unknown, with a median follow-up of 44 months. There were no factors associated with HER2 loss apart from age. On Kaplan-Meier analysis, estimated 5-year recurrence-free survival (RFS) and overall survival (OS) for patients with HER2-positive residual disease was 81% and 92%, respectively, and 74% (log rank p = 0.75) and 81% (p = 0.35) in patients with HER2-negative residual disease. CONCLUSION: The loss of HER2-positivity following NAT is not associated with worse 5-year RFS or OS. We do not recommend retesting HER2 status following NAT for the purpose of clinical management; these patients should complete targeted adjuvant therapy.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Terapia Neoadjuvante/mortalidade , Receptor ErbB-2/metabolismo , Adulto , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
19.
Pathol Oncol Res ; 27: 1609795, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34267603

RESUMO

This study was undertaken to investigate immunohistochemical expression of the senescence-associated secretory phenotype (SASP) in invasive breast cancer (IBC) tissues and to determine relationships between SASP positivity and tumor microenvironments and the clinicopathological characteristics of IBC. Immunohistochemistry for senescence markers, that is, high mobility group box-1 (HMGB1), p16, p15, and decoy receptor 2 (DCR2), was performed in tissue microarrays of 1140 IBC samples. Cases positive for at least one of these four markers were considered SASP-positive. Relations between SASP and tumor characteristics, including immune microenvironments (stromal tumor-infiltrating lymphocytes [sTILs] density and numbers of intraepithelial CD103-positive [iCD103 + ] lymphocytes) and clinical outcomes were retrospectively evaluated. HMGB1, p16, p15, or DCR2 was positive in 6.7%, 26.6%, 21.1%, and 26.5%, respectively, of the 1,140 cases. Six hundred and five (53.1%) cases were SASP positive, and SASP positivity was significantly associated with histologic grade 3, high-sTIL and iCD103 + lymphocyte counts, absence of ER or PR, and a high Ki-67 index. Although SASP did not predict breast cancer-specific survival (BCSS) or disease-free survival (DFS) in the entire cohort, SASP positivity in luminal A IBC was associated with poor BCSS and DFS. However, patients with SASP-positive TNBC showed better survival than those with SASP-negative TNBC. In multivariate analysis, SASP positivity was an independent prognostic factor in both luminal A IBC and TNBC, although the effect on prognosis was the opposite. In conclusion, SASP would be involved in the modulation of immune microenvironments and tumor progression in IBC, and its prognostic significance depends on molecular subtype.


Assuntos
Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/patologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral , Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/imunologia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Estudos Retrospectivos , Taxa de Sobrevida
20.
Pathol Oncol Res ; 27: 599894, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-34257555

RESUMO

Background: The objective was to explore the discordance in the expression of the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and Ki-67 between primary and recurrent/metastatic lesions in patients with early stage breast cancer as well as the prognostic impact. Method: Patients with early-stage primary breast cancer and confirmed recurrence/metastasis at Peking Union Medical College Hospital between January 2005 and August 2018 were screened. The details of discordance in each parameter between primary and recurrent/metastatic lesions and progression were recorded. Regression and survival analysis were applied to determine the association and clinical impact of the discordance. Results: We evaluated 75 patients. The discordance rate of ER, PR, HER2, and Ki-67 expression was 9.3, 14.7, 14.7, and 21.5%, respectively. Additionally, 66.7, 11.8, 14.3, and 0% of patients with Luminal A, Luminal B, HER2, and triple-negative primary tumors presented with a different subtype for the recurrent/metastatic tumors, respectively. No statistical difference in progression-free survival was observed according to the subtype of the recurrent or metastatic breast cancer (p > 0.05). Among 69 patients for whom treatment was adjusted after recurrence or metastasis, 66 patients remained recurrence-free during the follow-up period. Conclusion: For patients with early-stage breast cancer, the ER, PR, HER2, and Ki-67 expression profile for recurrent/metastatic tumors does not always match that of the primary tumor. After adjusting treatment according to the receptor expression in recurrent/metastatic lesions, most patients remained progression-free during the follow-up period.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/patologia , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/terapia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/secundário , Carcinoma Ductal de Mama/terapia , Carcinoma Lobular/metabolismo , Carcinoma Lobular/secundário , Carcinoma Lobular/terapia , Terapia Combinada , Feminino , Seguimentos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/metabolismo , Recidiva Local de Neoplasia/terapia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Adulto Jovem
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...