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1.
Sci Rep ; 13(1): 16742, 2023 10 05.
Artigo em Inglês | MEDLINE | ID: mdl-37798427

RESUMO

Targeting mitochondrial oxidative phosphorylation (OXPHOS) to treat cancer has been hampered due to serious side-effects potentially arising from the inability to discriminate between non-cancerous and cancerous mitochondria. Herein, comprehensive mitochondrial phenotyping was leveraged to define both the composition and function of OXPHOS across various murine cancers and compared to both matched normal tissues and other organs. When compared to both matched normal tissues, as well as high OXPHOS reliant organs like heart, intrinsic expression of the OXPHOS complexes, as well as OXPHOS flux were discovered to be consistently lower across distinct cancer types. Assuming intrinsic OXPHOS expression/function predicts OXPHOS reliance in vivo, these data suggest that pharmacologic blockade of mitochondrial OXPHOS likely compromises bioenergetic homeostasis in healthy oxidative organs prior to impacting tumor mitochondrial flux in a clinically meaningful way. Although these data caution against the use of indiscriminate mitochondrial inhibitors for cancer treatment, considerable heterogeneity was observed across cancer types with respect to both mitochondrial proteome composition and substrate-specific flux, highlighting the possibility for targeting discrete mitochondrial proteins or pathways unique to a given cancer type.


Assuntos
Neoplasias , Fosforilação Oxidativa , Camundongos , Humanos , Animais , Mitocôndrias/metabolismo , Metabolismo Energético , Neoplasias/genética , Neoplasias/metabolismo
2.
Am Surg ; 89(3): 407-413, 2023 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34190619

RESUMO

BACKGROUND: Phyllodes tumor (PT) is a rare fibroepithelial lesion of the breast with variable malignant potential. Black women have a higher incidence of a related benign tumor, fibroadenoma, but there are limited epidemiological data on PT. The aim of our study was to evaluate race-related differences in the clinicopathologic features and outcomes of PT. METHODS: Our institutional pathology database was queried for breast specimen reports from 01/2009 to 10/2019 to identify patients with a pathologic diagnosis of PT. Chart review and detailed slide review were performed to obtain clinical and histopathologic variables, respectively. RESULTS: Among twelve patients, two had malignant PT, three had borderline PT, and seven had benign PT. All patients with malignant and borderline PT were black, compared with 29% of those with benign PT. There were no apparent race-related differences in specific histopathologic features among black vs. non-black women with benign PT. Malignant and borderline PT were relatively larger than benign PT, with mean tumor sizes of 9.0 cm (standard deviation [SD] 4.7 cm), 12.2 cm (SD 9.4 cm), and 5.4 cm (SD 5.8 cm), respectively. Two women had a local recurrence, both of whom were black. DISCUSSION: In this single-institution retrospective study, we observed disproportionate rates of aggressive histopathologic features and disparate outcomes among black women with PT. A multi-institutional PT registry would facilitate improved knowledge about race-related differences in the presentation and outcomes of this rare tumor.


Assuntos
Neoplasias da Mama , Tumor Filoide , Feminino , Humanos , Tumor Filoide/diagnóstico , Estudos Retrospectivos , Mama/patologia , Neoplasias da Mama/patologia
3.
Front Oncol ; 12: 919880, 2022.
Artigo em Inglês | MEDLINE | ID: mdl-35756609

RESUMO

Hepatocellular carcinoma (HCC) is the most common form of liver cancer worldwide. Increasing evidence suggests that mitochondria play a central role in malignant metabolic reprogramming in HCC, which may promote disease progression. To comprehensively evaluate the mitochondrial phenotype present in HCC, we applied a recently developed diagnostic workflow that combines high-resolution respirometry, fluorometry, and mitochondrial-targeted nLC-MS/MS proteomics to cell culture (AML12 and Hepa 1-6 cells) and diethylnitrosamine (DEN)-induced mouse models of HCC. Across both model systems, CI-linked respiration was significantly decreased in HCC compared to nontumor, though this did not alter ATP production rates. Interestingly, CI-linked respiration was found to be restored in DEN-induced tumor mitochondria through acute in vitro treatment with P1, P5-di(adenosine-5') pentaphosphate (Ap5A), a broad inhibitor of adenylate kinases. Mass spectrometry-based proteomics revealed that DEN-induced tumor mitochondria had increased expression of adenylate kinase isoform 4 (AK4), which may account for this response to Ap5A. Tumor mitochondria also displayed a reduced ability to retain calcium and generate membrane potential across a physiological span of ATP demand states compared to DEN-treated nontumor or saline-treated liver mitochondria. We validated these findings in flash-frozen human primary HCC samples, which similarly displayed a decrease in mitochondrial respiratory capacity that disproportionately affected CI. Our findings support the utility of mitochondrial phenotyping in identifying novel regulatory mechanisms governing cancer bioenergetics.

4.
JCI Insight ; 7(13)2022 07 08.
Artigo em Inglês | MEDLINE | ID: mdl-35639484

RESUMO

Women of African ancestry suffer higher rates of breast cancer mortality compared with all other groups in the United States. Though the precise reasons for these disparities remain unclear, many recent studies have implicated a role for differences in tumor biology. Using an epitope-validated antibody against the endoplasmic reticulum-associated E3 ligase, gp78, we show that elevated levels of gp78 in patient breast cancer cells predict poor survival. Moreover, high levels of gp78 are associated with poor outcomes in both ER+ and ER- tumors, and breast cancers expressing elevated amounts of gp78 protein are enriched in gene expression pathways that influence cell cycle, metabolism, receptor-mediated signaling, and cell stress response pathways. In multivariate analysis adjusted for subtype and grade, gp78 protein is an independent predictor of poor outcomes in women of African ancestry. Furthermore, gene expression signatures, derived from patients stratified by gp78 protein expression, are strong predictors of recurrence and pathological complete response in retrospective clinical trial data and share many common features with gene sets previously identified to be overrepresented in breast cancers based on race. These findings implicate a prominent role for gp78 in tumor progression and offer insights into our understanding of racial differences in breast cancer outcomes.


Assuntos
Neoplasias da Mama , Ubiquitina-Proteína Ligases , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Retículo Endoplasmático/metabolismo , Feminino , Humanos , Estudos Retrospectivos , Transdução de Sinais , Ubiquitina-Proteína Ligases/metabolismo
5.
Arch Pathol Lab Med ; 146(10): 1258-1267, 2022 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-35119458

RESUMO

CONTEXT.­: The Oncotype DX Recurrence Score (RS) predicts recurrence and chemotherapy benefit in early-stage estrogen receptor-positive breast cancer patients. Cost and unavailability are 2 major disadvantages of the assay. Multiple models have been developed to predict the RS. OBJECTIVE.­: To predict RS based on histopathologic and biomarker features, and to measure concordance and correlation with RS of the following 3 algorithms: breast cancer prognostic score, Magee0, and Magee2. DESIGN.­: Breast cancer cases with available RSs were reviewed (n = 442). RS categories were stratified by pathologic and biomarker variables. Histopathologic and biomarker data were abstracted from pathology reports, and RS was calculated by each model. Correlation and concordance between models and RS were calculated. RESULTS.­: Less than 5% of breast cancers with lobular features, low-grade tumors, carcinomas with high progesterone receptor content, or luminal A tumors had an RS greater than 25. Breast cancer prognostic score, Magee0, and Magee2 demonstrated correlation coefficients with RS of 0.63, 0.61, and 0.62, respectively. Two-step discordances were uncommon. When an RS of 25 was used to separate high-risk from non-high-risk cases, concordance rates of 86% to 88% were achieved. CONCLUSIONS.­: High RS was observed only in a small percentage of pure or mixed lobular carcinomas, low-grade or luminal A tumors, and tumors with high progesterone receptor expression, suggesting that these cancers may not require Oncotype testing. All 3 surrogate models demonstrated comparable correlation and high concordance with the RS when a cutoff of 25 was used, suggesting their utility in cases where the actual RS is unavailable.


Assuntos
Neoplasias da Mama , Receptores de Progesterona , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Feminino , Perfilação da Expressão Gênica/métodos , Humanos , Recidiva Local de Neoplasia/patologia , Prognóstico , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo
6.
Am Surg ; 88(5): 929-935, 2022 May.
Artigo em Inglês | MEDLINE | ID: mdl-34964694

RESUMO

INTRODUCTION: Although minimally invasive surgery (MIS) has clearly been associated with improved colorectal surgery outcomes, not all populations benefit from this approach. Using a national database, we analyzed both, the trend in the utilization of MIS for diverticulitis and differences in utilization by race. METHODS: Colon-targeted participant user files (PUFs) from 2012 to 18 were linked to respective PUFs in National Surgical Quality Improvement Project. Patients undergoing colectomy for acute diverticulitis or chronic diverticular disease were included. Surgical approach was stratified by race and year. To adjust for confounding and estimate the association of covariates with approach, data were fit using multivariable binary logistic regression main effects model. Using a joint effects model, we evaluated whether the odds of a particular approach over time was differentially affected by race. RESULTS: Of the 46 713 patients meeting inclusion criteria, 83% were white, with 7% black and 10% other. Over the study period, there was a decrease in the rate of open colectomy of about 5% P < .001, and increase in the rate of utilization of laparoscopic and robotic approaches (RC) P < .0001. After adjusting for confounders, black race was associated with open surgery P < .0001. CONCLUSION: There is disparity in the utilization of MIS for diverticulitis. Further research into the reasons for this disparity is critical to ensure known benefits of MIC are realized across all races.


Assuntos
Doenças Diverticulares , Diverticulite , Laparoscopia , Colectomia , Diverticulite/cirurgia , Humanos , Procedimentos Cirúrgicos Minimamente Invasivos , Complicações Pós-Operatórias , Estudos Retrospectivos
7.
Am Surg ; 88(4): 746-751, 2022 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-34792413

RESUMO

BACKGROUND: The literature is replete with studies that define the nexus of quantity and quality in complex surgical operations. These observations have heralded a call for centralization of care to high-volume centers. The purpose of this study was to chronicle improvements in quality associated with pancreaticoduodenectomy (PD) as a rural hospital matures from a low- to very high-volume center. METHODS: A retrospective review of a prospective pancreatic surgery database was undertaken from July 2007 to June 2020. Annual periods were characterized as low (≤12/year), high (13-29/year), and very high volume (≥30/year). Data for the following quality benchmarks were aggregated and compared: length of stay (LOS), 30-day readmissions, 30-day mortality, and 1- and 3-year survival. A subgroup analysis was undertaken in those patients undergoing PD for adenocarcinoma detailing margin status and number of lymph nodes harvested. Outcomes were compared using the Fisher's exact and Student's t-test. RESULTS: 375 PD were completed over the 13-year period; 62.1% were undertaken for ductal adenocarcinoma. There was a significant decrease in LOS and 30-day readmissions as the institution matured toward very high volume. There were no significant differences in 30-day mortality, 1- and 3-year survival, or margin negativity rates associated with volume. Extent of lymph node harvest significantly improved as institutional experience increased. DISCUSSION: Our pancreatic surgery program matured rapidly from low to very high volume with institutional commitment and dedicated resources. As the institution matured, operational efficiencies and surgical quality improved. Not unexpectedly, biology trumped volume as reflected in 1- and 3-year survival rates.


Assuntos
Adenocarcinoma , Neoplasias Pancreáticas , Adenocarcinoma/patologia , Hospitais Rurais , Humanos , Tempo de Internação , Pancreatectomia , Neoplasias Pancreáticas/patologia , Pancreaticoduodenectomia , Estudos Prospectivos , Estudos Retrospectivos
8.
Elife ; 102021 06 16.
Artigo em Inglês | MEDLINE | ID: mdl-34132194

RESUMO

Currently there is great interest in targeting mitochondrial oxidative phosphorylation (OXPHOS) in cancer. However, notwithstanding the targeting of mutant dehydrogenases, nearly all hopeful 'mito-therapeutics' cannot discriminate cancerous from non-cancerous OXPHOS and thus suffer from a limited therapeutic index. Using acute myeloid leukemia (AML) as a model, herein, we leveraged an in-house diagnostic biochemical workflow to identify 'actionable' bioenergetic vulnerabilities intrinsic to cancerous mitochondria. Consistent with prior reports, AML growth and proliferation was associated with a hyper-metabolic phenotype which included increases in basal and maximal respiration. However, despite having nearly 2-fold more mitochondria per cell, clonally expanding hematopoietic stem cells, leukemic blasts, as well as chemoresistant AML were all consistently hallmarked by intrinsic OXPHOS limitations. Remarkably, by performing experiments across a physiological span of ATP free energy, we provide direct evidence that leukemic mitochondria are particularly poised to consume ATP. Relevant to AML biology, acute restoration of oxidative ATP synthesis proved highly cytotoxic to leukemic blasts, suggesting that active OXPHOS repression supports aggressive disease dissemination in AML. Together, these findings argue against ATP being the primary output of leukemic mitochondria and provide proof-of-principle that restoring, rather than disrupting, OXPHOS may represent an untapped therapeutic avenue for combatting hematological malignancy and chemoresistance.


Assuntos
Metabolismo Energético/fisiologia , Leucemia Mieloide Aguda , Fosforilação Oxidativa , Trifosfato de Adenosina/metabolismo , Adolescente , Adulto , Idoso , Feminino , Humanos , Leucemia Mieloide Aguda/metabolismo , Leucemia Mieloide Aguda/fisiopatologia , Masculino , Pessoa de Meia-Idade , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Adulto Jovem
9.
Breast Cancer Res Treat ; 187(3): 805-814, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33609208

RESUMO

PURPOSE: American Joint Committee on Cancer (AJCC) clinical staging is used to estimate breast cancer prognosis, but individual patient survival within each stage varies considerably by age at diagnosis. We hypothesized that the addition of age at diagnosis to the staging schema will enable more refined risk stratification. METHODS: We performed a retrospective population analysis of adult women diagnosed with invasive breast cancer between 2010 and 2015 registered in SEER. Multivariable Cox hazards models were used to evaluate the association of AJCC 8th edition clinical prognostic stage (CPS) and age with risk of overall mortality. Separate hierarchical models were fit to the data: Model 1: CPS alone; Model 2: CPS + age + age2; and Model 3: CPS + age + age2 + CPS x age + CPS x age2. Models were compared by the Akaike information criterion (AIC), the c-statistic for time-dependent receiver operator characteristic curves, and category-free net reclassification improvement (NRI). Internal validation was performed using bootstrapping samples. RESULTS: Among 86,637 women, the median follow-up was 36 months and 3-year overall survival was 91.9% ± 0.1%. Age significantly modified the effect of CPS on survival (p < 0.0001). Model 3 was the most precise, with the lowest AIC (126,619.63), the highest c-statistic (0.8212, standard error 0.0187), and superior NRI indices. CONCLUSION: Age at diagnosis is a highly prognostic variable that warrants consideration for inclusion in future editions of the AJCC Breast Cancer Staging Manual.


Assuntos
Neoplasias da Mama , Adulto , Mama/patologia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Pré-Escolar , Feminino , Humanos , Estadiamento de Neoplasias , Prognóstico , Estudos Retrospectivos
10.
Commun Biol ; 4(1): 150, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33526872

RESUMO

The use of digital pathology for the histomorphologic profiling of pathological specimens is expanding the precision and specificity of quantitative tissue analysis at an unprecedented scale; thus, enabling the discovery of new and functionally relevant histological features of both predictive and prognostic significance. In this study, we apply quantitative automated image processing and computational methods to profile the subcellular distribution of the multi-functional transcriptional regulator, Kaiso (ZBTB33), in the tumors of a large racially diverse breast cancer cohort from a designated health disparities region in the United States. Multiplex multivariate analysis of the association of Kaiso's subcellular distribution with other breast cancer biomarkers reveals novel functional and predictive linkages between Kaiso and the autophagy-related proteins, LC3A/B, that are associated with features of the tumor immune microenvironment, survival, and race. These findings identify effective modalities of Kaiso biomarker assessment and uncover unanticipated insights into Kaiso's role in breast cancer progression.


Assuntos
Neoplasias da Mama/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Fatores de Transcrição/metabolismo , Microambiente Tumoral , Automação Laboratorial , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Feminino , Imunofluorescência , Regulação Neoplásica da Expressão Gênica , Humanos , Interpretação de Imagem Assistida por Computador , Microscopia de Fluorescência , Proteínas Associadas aos Microtúbulos/genética , Prognóstico , Estudos Retrospectivos , Medição de Risco , Fatores de Risco , Transdução de Sinais , Fatores de Tempo , Análise Serial de Tecidos , Fatores de Transcrição/genética , Evasão Tumoral , Estados Unidos/epidemiologia
11.
IJU Case Rep ; 4(1): 49-52, 2021 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-33426498

RESUMO

INTRODUCTION: Renal cell carcinoma is often discovered at an early stage due to the increased use of imaging studies in the current era; therefore, its presentation as a gigantic renal cell carcinoma is rarely encountered. CASE PRESENTATION: A 59-year-old male presented to our hospital due to dizziness, fatigue, and increasing abdominal distension. A computed tomography scan showed an extremely large mass occupying most of the abdomen and pelvis. Surgical resection of the mass was performed. The largely cavitary mass with fibrous capsule was 43 cm and 13.0 kg, and contained a large amount of necrotic tissue. A portion of the left kidney was identified at the periphery of the mass, indicating that the tumor was arising from the left kidney. The final pathologic diagnosis was type 1 papillary renal cell carcinoma. CONCLUSION: To the best of our knowledge, this tumor is the world's largest malignant renal tumor.

12.
JAMA Surg ; 156(3): 239-245, 2021 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-33326009

RESUMO

Importance: Although optimal access is accepted as the key to quality care, an accepted methodology to ascertain potential disparities in surgical access has not been defined. Objective: To develop a systematic approach to detect surgical access disparities. Design, Setting, and Participants: This cross-sectional study used publicly available data from the Health Cost and Utilization Project State Inpatient Database from 2016. Using the surgical rate observed in the 5 highest-ranked counties (HRCs), the expected surgical rate in the 5 lowest-ranked counties (LRCs) in North Carolina were calculated. Patients 18 years and older who underwent an inpatient general surgery procedure and patients who underwent emergency inpatient cholecystectomy, herniorrhaphy, or bariatric surgery in 2016 were included. Data were collected from January to December 2016, and data were analyzed from March to July 2020. Exposures: Health outcome county rank as defined by the Robert Wood Johnson Foundation. Main Outcomes and Measures: The primary outcome was the proportional surgical ratio (PSR), which was the disparity in surgical access defined as the observed number of surgical procedures in the 5 LRCs relative to the expected number of procedures using the 5 HRCs as the standardized reference population. Results: In 2016, approximately 1.9 million adults lived in the 5 HRCs, while approximately 246 854 lived in the 5 LRCs. A total of 28 924 inpatient general surgical procedures were performed, with 4521 being performed in those living in the 5 LRCs and 24 403 in those living in the 5 HRCs. The rate of general surgery in the 5 HRCs was 13.09 procedures per 1000 population. Using the 5 HRCs as the reference, the PSR for the 5 LRCs was 1.40 (95% CI, 1.35-1.44). For emergent/urgent cholecystectomy, the PSR for the 5 LRCs was 2.26 (95% CI, 2.02-2.51), and the PSR for emergent/urgent herniorrhaphy was 1.83 (95% CI, 1.33-2.45). Age-adjusted rate of obesity (body mass index [calculated as weight in kilograms divided by height in meters squared] greater than 30), on average, was 36.6% (SD, 3.4) in the 5 LRCs vs 25.4% (SD, 4.6) in the 5 HRCs (P = .002). The rate of bariatric surgery in the 5 HRCs was 33.07 per 10 000 population with obesity. For the 5 LRCs, the PSR was 0.60 (95% CI, 0.51-0.69). Conclusions and Relevance: The PSR is a systematic approach to define potential disparities in surgical access and should be useful for identifying, investigating, and monitoring interventions intended to mitigate disparities in surgical access that effects the health of vulnerable populations.


Assuntos
Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Disparidades em Assistência à Saúde/estatística & dados numéricos , Procedimentos Cirúrgicos Operatórios/estatística & dados numéricos , Adulto , Idoso , Estudos Transversais , Bases de Dados Factuais , Feminino , Hospitalização/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , North Carolina , Utilização de Procedimentos e Técnicas , Fatores Socioeconômicos
13.
Biochim Biophys Acta Gen Subj ; 1865(2): 129784, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33166603

RESUMO

BACKGROUND: Metastasis and mortality remain high among breast cancer patients with the claudin-low subtype because these tumors are aggressive, chemoresistant, and lack targeted therapies. Our objective was to utilize discovery-based proteomics to identify proteins associated with claudin-low primary and metastatic tumors to gain insight into pathways and mechanisms of tumor progression. METHODS: We used nano-LC-MS/MS proteomics to analyze orthotopic and metastatic tumors from the syngeneic murine T11 tumor model, which displays gene expression profiles mirroring human claudin-low tumors. Galectin-1 identity, expression and spatial distribution were investigated by biochemical and immunochemical methods and MALDI/IMS. RNA seq data from mouse and human tumors in our study and publicly available microarray data were analyzed for differential galectin-1 expression across breast cancer subtypes. RESULTS: Galectin-1, an N-acetyllactosamine-binding protein, exhibited the highest sequence coverage and high abundance rank order among nano-LC-MS/MS-identified proteins shared by T11 claudin-low tumors but not normal tissue. Label-free quantitation, Western immunoblot and ELISA confirmed galectin-1 identity and significant differential expression. MALDI/IMS spatial mapping and immunohistochemistry detected galectin-1 in T11 metastatic lung foci. Immunohistochemistry of human claudin-low tumors demonstrated intermediate-to-high intensity galectin-1 staining of tumor and stroma. Gene expression analysis of mouse and human tumors found the highest galectin-1 levels in the claudin-low breast cancer subtype. CONCLUSIONS: Proteomics and genomics reveal high expression of galectin-1 protein and RNA in primary and metastatic claudin-low breast cancer. GENERAL SIGNIFICANCE: This work endorses proteomic approaches in cancer research and supports further investigations of the function and significance of galectin-1 overexpression in claudin-low tumor progression.


Assuntos
Neoplasias da Mama/patologia , Claudinas/análise , Galectina 1/análise , Animais , Neoplasias da Mama/genética , Claudinas/genética , Feminino , Galectina 1/genética , Regulação Neoplásica da Expressão Gênica , Humanos , Imuno-Histoquímica , Camundongos Endogâmicos BALB C , Proteômica
14.
Cancer Epidemiol Biomarkers Prev ; 29(5): 1049-1057, 2020 05.
Artigo em Inglês | MEDLINE | ID: mdl-32098892

RESUMO

BACKGROUND: Reduction in breast density may be a biomarker of endocrine therapy (ET) efficacy. Our objective was to assess the impact of race on ET-related changes in volumetric breast density (VBD). METHODS: This retrospective cohort study assessed longitudinal changes in VBD measures in women with estrogen receptor-positive invasive breast cancer treated with ET. VBD, the ratio of fibroglandular volume (FGV) to breast volume (BV), was measured using Volpara software. Changes in measurements were evaluated using a multivariable linear mixed effects model. RESULTS: Compared with white women (n = 191), black women (n = 107) had higher rates of obesity [mean ± SD body mass index (BMI) 34.5 ± 9.1 kg/m2 vs. 30.6 ± 7.0 kg/m2, P < 0.001] and premenopausal status (32.7% vs. 16.7%, P = 0.002). Age- and BMI-adjusted baseline FGV, BV, and VBD were similar between groups. Modeled longitudinal changes were also similar: During a follow-up of 30.7 ± 15.0 months (mean ± SD), FGV decreased over time in premenopausal women (slope = -0.323 cm3; SE = 0.093; P = 0.001), BV increased overall (slope = 2.475 cm3; SE = 0.483; P < 0.0001), and VBD decreased (premenopausal slope = -0.063%, SE = 0.011; postmenopausal slope = -0.016%, SE = 0.004; P < 0.0001). Race was not significantly associated with these longitudinal changes, nor did race modify the effect of time on these changes. Higher BMI was associated with lower baseline VBD (P < 0.0001). Among premenopausal women, VBD declined more steeply for women with lower BMI (time × BMI, P = 0.0098). CONCLUSIONS: Race does not appear to impact ET-related longitudinal changes in VBD. IMPACT: Racial disparities in estrogen receptor-positive breast cancer recurrence and mortality may not be explained by differential declines in breast density due to ET.


Assuntos
Antineoplásicos Hormonais/uso terapêutico , Densidade da Mama/efeitos dos fármacos , Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/epidemiologia , Obesidade/epidemiologia , Negro ou Afro-Americano/estatística & dados numéricos , Idoso , Antineoplásicos Hormonais/farmacologia , Índice de Massa Corporal , Mama/diagnóstico por imagem , Mama/efeitos dos fármacos , Mama/patologia , Mama/fisiopatologia , Densidade da Mama/fisiologia , Neoplasias da Mama/patologia , Neoplasias da Mama/fisiopatologia , Feminino , Seguimentos , Disparidades nos Níveis de Saúde , Humanos , Estudos Longitudinais , Mamografia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/fisiopatologia , Receptores de Estrogênio/análise , Receptores de Estrogênio/metabolismo , Estudos Retrospectivos , Resultado do Tratamento , População Branca/estatística & dados numéricos
15.
Clin Cancer Res ; 26(8): 1905-1914, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-31911546

RESUMO

PURPOSE: Compared with their European American (EA) counterparts, African American (AA) women are more likely to die from breast cancer in the United States. This disparity is greatest in hormone receptor-positive subtypes. Here we uncover biological factors underlying this disparity by comparing functional expression and prognostic significance of master transcriptional regulators of luminal differentiation. EXPERIMENTAL DESIGN: Data and biospecimens from 262 AA and 293 EA patients diagnosed with breast cancer from 2001 to 2010 at a major medical center were analyzed by IHC for functional biomarkers of luminal differentiation, including estrogen receptor (ESR1) and its pioneer factors, FOXA1 and GATA3. Integrated comparison of protein levels with network-level gene expression analysis uncovered predictive correlations with race and survival. RESULTS: Univariate or multivariate HRs for overall survival, estimated from digital IHC scoring of nuclear antigen, show distinct differences in the magnitude and significance of these biomarkers to predict survival based on race: ESR1 [EA HR = 0.47; 95% confidence interval (CI), 0.31-0.72 and AA HR = 0.77; 95% CI, 0.48-1.18]; FOXA1 (EA HR = 0.38; 95% CI, 0.23-0.63 and AA HR = 0.53; 95% CI, 0.31-0.88), and GATA3 (EA HR = 0.36; 95% CI, 0.23-0.56; AA HR = 0.57; CI, 0.56-1.4). In addition, we identify genes in the downstream regulons of these biomarkers highly correlated with race and survival. CONCLUSIONS: Even within clinically homogeneous tumor groups, regulatory networks that drive mammary luminal differentiation reveal race-specific differences in their association with clinical outcome. Understanding these biomarkers and their downstream regulons will elucidate the intrinsic mechanisms that drive racial disparities in breast cancer survival.


Assuntos
População Negra/genética , Neoplasias da Mama/mortalidade , Receptor alfa de Estrogênio/metabolismo , Fator de Transcrição GATA3/metabolismo , Regulação Neoplásica da Expressão Gênica , Fator 3-alfa Nuclear de Hepatócito/metabolismo , População Branca/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/etnologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Feminino , Disparidades nos Níveis de Saúde , Humanos , Imuno-Histoquímica/métodos , Pessoa de Meia-Idade , Taxa de Sobrevida , Estados Unidos
16.
Cell Death Dis ; 10(10): 689, 2019 09 18.
Artigo em Inglês | MEDLINE | ID: mdl-31534138

RESUMO

The C-terminal binding protein (CtBP) is an NADH-dependent dimeric family of nuclear proteins that scaffold interactions between transcriptional regulators and chromatin-modifying complexes. Its association with poor survival in several cancers implicates CtBP as a promising target for pharmacological intervention. We employed computer-assisted drug design to search for CtBP inhibitors, using quantitative structure-activity relationship (QSAR) modeling and docking. Functional screening of these drugs identified 4 compounds with low toxicity and high water solubility. Micro molar concentrations of these CtBP inhibitors produces significant de-repression of epigenetically silenced pro-epithelial genes, preferentially in the triple-negative breast cancer cell line MDA-MB-231. This epigenetic reprogramming occurs through eviction of CtBP from gene promoters; disrupted recruitment of chromatin-modifying protein complexes containing LSD1, and HDAC1; and re-wiring of activating histone marks at targeted genes. In functional assays, CtBP inhibition disrupts CtBP dimerization, decreases cell migration, abolishes cellular invasion, and improves DNA repair. Combinatorial use of CtBP inhibitors with the LSD1 inhibitor pargyline has synergistic influence. Finally, integrated correlation of gene expression in breast cancer patients with nuclear levels of CtBP1 and LSD1, reveals new potential therapeutic vulnerabilities. These findings implicate a broad role for this class of compounds in strategies for epigenetically targeted therapeutic intervention.


Assuntos
Oxirredutases do Álcool/genética , Neoplasias da Mama/genética , Proteínas de Ligação a DNA/genética , Epigênese Genética/genética , Feminino , Humanos
17.
Breast Cancer Res Treat ; 177(3): 713-722, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31297648

RESUMO

PURPOSE: The relationship between age at diagnosis and breast cancer-specific mortality (BCSM) is unclear. The aim of this study was to examine the nature of this relationship using rigorous statistical methodology. METHODS: A historical cohort study of adult women with invasive breast cancer in the SEER database from 2000 to 2015 was conducted. Multivariable Cox's cause-specific hazards model was used to evaluate the association of age at diagnosis with risk of BCSM. Functional relationship of age was assessed using cumulative sums of Martingale residuals and the Kolmogorov-type supremum test. RESULTS: A total of 206,332 women were eligible for study. Mean age at diagnosis was 59.7 ± 13.8 years. Median follow-up was 80 months. During the study period, 21,771 women (10.6%) died from breast cancer and 18,566 (9.0%) died from other causes. Cumulative incidence of BCSM at 120 months post-diagnosis was 14.4% (95% CI 14.2-14.6%). Age was found to be quadratically related to the risk of BCSM (p < 0.001), with a nadir at 45 years of age. The final Cox model suggests that a 30-year-old woman has approximately the same adjusted BCSM risk (HR 1.187, 95% CI 1.187-1.188) as a 60-year-old woman (HR 1.174, 95% CI 1.174-1.175). CONCLUSIONS: Women diagnosed with breast cancer at the extremes of age suffer disproportionate rates of cancer-specific mortality. The relationship between age at diagnosis and adjusted risk of BCSM is complex, consistent with a quadratic function. With the growing appreciation for breast cancer as a heterogeneous disease, it is essential to accurately address age as a prognostic risk factor in predictive models.


Assuntos
Idade de Início , Neoplasias da Mama/epidemiologia , Idoso , Biomarcadores Tumorais , Neoplasias da Mama/etiologia , Neoplasias da Mama/mortalidade , Feminino , Humanos , Pessoa de Meia-Idade , Mortalidade , Análise Multivariada , Gradação de Tumores , Estadiamento de Neoplasias , Modelos de Riscos Proporcionais , Vigilância em Saúde Pública , Programa de SEER
18.
Breast Cancer Res Treat ; 177(1): 155-164, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31127469

RESUMO

PURPOSE: Current NCCN guidelines for occult breast cancer (OBC) recommend modified radical mastectomy, with the option for breast preservation with radiation instead of mastectomy for N1 patients. Our aim was to compare the effect of local therapy-mastectomy versus breast radiation-on breast cancer-specific mortality (BCSM) in a contemporary cohort of OBC patients of all nodal stages. METHODS: Competing risk analyses were performed to evaluate the effect of local therapy, nodal stage, and other demographic and clinical prognostic variables on risk of BCSM for women registered in the SEER database with T0N+M0 breast cancer from 2004 to 2015. RESULTS: Of the 353 women with OBC who underwent axillary nodal dissection, 152 received breast radiation and 201 underwent mastectomy. Overall, 57.5% had N1 disease, 54.4% had estrogen receptor (ER) positive tumors, 80.7% were white, and 88.1% received chemotherapy. Women treated with radiation were older (p < 0.001). The two groups were comparable with respect to all other variables analyzed. During a median follow-up of 66 months, 32 women died from breast cancer (radiation: 11, mastectomy: 21). Five-year cumulative incidence of BCSM was 8.0% ± 2.6% with radiation versus 10.9% ± 2.6% with mastectomy (p = 0.309). On multivariate analysis, independent predictors of BCSM included older age, higher N stage, and ER negativity, but the type of local therapy was not significantly associated with outcome. CONCLUSIONS: These results suggest that breast preservation is a reasonable alternative to mastectomy for OBC patients, regardless of nodal stage.


Assuntos
Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Adulto , Idoso , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Terapia Combinada , Feminino , Humanos , Estimativa de Kaplan-Meier , Metástase Linfática , Mastectomia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Vigilância da População , Prognóstico , Modelos de Riscos Proporcionais , Radioterapia Adjuvante , Programa de SEER , Resultado do Tratamento
20.
J Cancer Educ ; 34(2): 277-284, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-29150748

RESUMO

Cancer has become the leading cause of death in North Carolina (NC) (North Carolina DHHS, State Center for Health Statistics 2015) and the eastern region of North Carolina (ENC) has experienced greater cancer mortality than the remainder of the state. The Pitt County Breast Wellness Initiative-Education (PCBWI-E) provides culturally tailored breast cancer education and navigation to screening services for uninsured/underinsured women in Pitt and Edgecombe Counties in ENC. PCBWI-E created a network of 23 lay breast health educators, and has educated 735 women on breast health and breast cancer screening guidelines. Navigation services have been provided to 365 women, of which 299 were given breast health assessments, 193 were recommended for a mammogram, and 138 were screened. We have identified five lessons learned to share in the successful implementation of a community-based breast cancer screening intervention: (1) community partnerships are critical for successful community-based cancer screening interventions; (2) assuring access to free or low-cost screening and appropriate follow-up should precede interventions to promote increased use of breast cancer screening; (3) the reduction of system-based barriers is effective in increasing cancer screening; (4) culturally tailored interventions can overcome barriers to screening for diverse racial/ethnic and socioeconomic groups; and (5) multi-component interventions that include multiple community health strategies are effective in increasing screening.


Assuntos
Neoplasias da Mama/prevenção & controle , Agentes Comunitários de Saúde/educação , Detecção Precoce de Câncer , Educação em Saúde/métodos , Acessibilidade aos Serviços de Saúde , Currículo , Feminino , Humanos , Mamografia/estatística & dados numéricos , Pessoas sem Cobertura de Seguro de Saúde , Pessoa de Meia-Idade , North Carolina , Saúde Pública , População Rural
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