RESUMEN
BACKGROUND: Oestrogen receptor (ER)- and progesterone receptor (PR)-negative (ER-PR-) breast cancer is associated with poorer prognosis compared with other breast cancer subtypes. High parity has been associated with an increased risk of ER-PR- cancer, but emerging evidence suggests that breastfeeding may reduce this risk. Whether this potential breastfeeding benefit extends to women at high risk of breast cancer remains critical to understand for prevention. METHODS: Using population-based ascertained cases (n=4011) and controls (2997) from the Breast Cancer Family Registry, we examined reproductive risk factors in relation to ER and PR status. RESULTS: High parity (≥3 live births) without breastfeeding was positively associated only with ER-PR- tumours (odds ratio (OR)=1.57, 95% confidence interval (CI), 1.10-2.24); there was no association with parity in women who breastfed (OR=0.93, 95% CI 0.71-1.22). Across all race/ethnicities, associations for ER-PR- cancer were higher among women who did not breastfeed than among women who did. Oral contraceptive (OC) use before 1975 was associated with an increased risk of ER-PR- cancer only (OR=1.32, 95% CI 1.04-1.67). For women who began OC use in 1975 or later there was no increased risk. CONCLUSIONS: Our findings support that there are modifiable factors for ER-PR- breast cancer and that breastfeeding in particular may mitigate the increased risk of ER-PR- cancers seen from multiparity.
Asunto(s)
Neoplasias de la Mama/metabolismo , Receptores de Estrógenos/deficiencia , Receptores de Progesterona/deficiencia , Reproducción/fisiología , Adulto , Australia/epidemiología , Lactancia Materna/estadística & datos numéricos , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/genética , California/epidemiología , Estudios de Casos y Controles , Anticonceptivos Orales/administración & dosificación , Femenino , Humanos , Persona de Mediana Edad , Ontario/epidemiología , Receptores de Estrógenos/genética , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/genética , Receptores de Progesterona/metabolismo , Sistema de Registros , Factores de RiesgoRESUMEN
Mapping of homozygous deletions on human chromosome 10q23 has led to the isolation of a candidate tumor suppressor gene, PTEN, that appears to be mutated at considerable frequency in human cancers. In preliminary screens, mutations of PTEN were detected in 31% (13/42) of glioblastoma cell lines and xenografts, 100% (4/4) of prostate cancer cell lines, 6% (4/65) of breast cancer cell lines and xenografts, and 17% (3/18) of primary glioblastomas. The predicted PTEN product has a protein tyrosine phosphatase domain and extensive homology to tensin, a protein that interacts with actin filaments at focal adhesions. These homologies suggest that PTEN may suppress tumor cell growth by antagonizing protein tyrosine kinases and may regulate tumor cell invasion and metastasis through interactions at focal adhesions.
Asunto(s)
Cromosomas Humanos Par 10 , Genes Supresores de Tumor , Mutación , Neoplasias/genética , Monoéster Fosfórico Hidrolasas , Proteínas Tirosina Fosfatasas/genética , Proteínas Supresoras de Tumor , Secuencia de Aminoácidos , Neoplasias Encefálicas/genética , Neoplasias de la Mama/genética , Mapeo Cromosómico , Femenino , Mutación del Sistema de Lectura , Glioblastoma/genética , Humanos , Masculino , Proteínas de Microfilamentos/química , Datos de Secuencia Molecular , Trasplante de Neoplasias , Fosfohidrolasa PTEN , Fosfotirosina/metabolismo , Neoplasias de la Próstata/genética , Proteínas Tirosina Fosfatasas/química , Proteínas Tirosina Fosfatasas/fisiología , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Tensinas , Trasplante Heterólogo , Células Tumorales CultivadasRESUMEN
INTRODUCTION: The PI3K/AKT/mTOR pathway is an oncogenic driver in breast cancer (BC). In this multi-center, pre-surgical study, we evaluated the tissue effects of the AKT inhibitor MK-2206 in women with stage I-III BC. MATERIALS AND METHODS: Two doses of weekly oral MK2206 were administered at days - 9 and - 2 before surgery. The primary endpoint was reduction of pAktSer473 in breast tumor tissue from diagnostic biopsy to surgery. Secondary endpoints included changes in PI3K/AKT pathway tumor markers, tumor proliferation (ki-67), insulin growth factor pathway blood markers, pharmacokinetics (PK), genomics, and MK-2206 tolerability. Paired t tests were used to compare biomarker changes in pre- and post-MK-2206, and two-sample t tests to compare with prospectively accrued untreated controls. RESULTS: Despite dose reductions, the trial was discontinued after 12 patients due to grade III rash, mucositis, and pruritus. While there was a trend to reduction in pAKT after MK-2206 (p = 0.06), there was no significant change compared to controls (n = 5, p = 0.65). After MK-2206, no significant changes in ki-67, pS6, PTEN, or stathmin were observed. There was no significant association between dose level and PK (p = 0.11). Compared to controls, MK-2206 significantly increased serum glucose (p = 0.02), insulin (p < 0.01), C-peptide (p < 0.01), and a trend in IGFBP-3 (p = 0.06). CONCLUSION: While a trend to pAKT reduction after MK-2206 was observed, there was no significant change compared to controls. However, the accrued population was limited, due to toxicity being greater than expected. Pre-surgical trials can identify in vivo activity in the early drug development, but side effects must be considered in this healthy population.
Asunto(s)
Neoplasias de la Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/tratamiento farmacológico , Compuestos Heterocíclicos con 3 Anillos/uso terapéutico , Proteínas Proto-Oncogénicas c-akt/antagonistas & inhibidores , Adulto , Anciano , Biomarcadores/sangre , Biomarcadores/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Evaluación de Medicamentos , Femenino , Compuestos Heterocíclicos con 3 Anillos/efectos adversos , Compuestos Heterocíclicos con 3 Anillos/farmacología , Humanos , Persona de Mediana Edad , Estadificación de Neoplasias , New York , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Transducción de Señal/efectos de los fármacosRESUMEN
PURPOSE: Reverse Phase Protein Array (RPPA) is a high-throughput antibody-based technique to assess cellular protein activity. The goal of this study was to assess protein marker changes by RPPA in tumor tissue from a pre-surgical metformin trial in women with operable breast cancer (BC). METHODS: In an open-label trial, metformin 1500-mg PO daily was administered prior to resection in 35 non-diabetic patients with stage 0-III BC, body mass index ≥25 kg/m2. For RPPA, formalin-fixed paraffin-embedded (FFPE) samples were probed with 160 antibodies. Paired and two-sample t-tests were performed (p ≤ 0.05). Multiple comparisons were adjusted for by fixing the false discovery rate at 25 %. We evaluated whether pre- and post-metformin changes of select markers by RPPA were identified by immunohistochemistry (IHC) in these samples. We also assessed for these changes by western blot in metformin-treated BC cell lines. RESULTS: After adjusting for multiple comparisons in the 32 tumors from metformin-treated patients vs. 34 untreated historical controls, 11 proteins were significantly different between cases vs. CONTROLS: increases in Raptor, C-Raf, Cyclin B1, Cyclin D1, TRFC, and Syk; and reductions in pMAPKpT202,Y204, JNKpT183,pT185, BadpS112, PKC.alphapS657, and SrcpY416. Cyclin D1 change after metformin by IHC was not observed. In cell lines, reductions in JNKpT183 and BadpS112 were seen, with no change in Cyclin D1 or Raptor. CONCLUSIONS: These results suggest that metformin modulates apoptosis/cell cycle, cell signaling, and invasion/motility. These findings should be assessed in larger metformin trials. If confirmed, associations between these changes and BC clinical outcome should be evaluated. CLINICALTRIALS. GOV IDENTIFIER: NCT00930579.
Asunto(s)
Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Carcinoma Intraductal no Infiltrante/metabolismo , Metformina/farmacología , Análisis por Matrices de Proteínas/métodos , Proteómica/métodos , Apoptosis/efectos de los fármacos , Western Blotting , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Carcinoma Intraductal no Infiltrante/tratamiento farmacológico , Carcinoma Intraductal no Infiltrante/patología , Ciclo Celular/efectos de los fármacos , Estudios de Cohortes , Femenino , Estudios de Seguimiento , Humanos , Hipoglucemiantes/farmacología , Técnicas para Inmunoenzimas , Invasividad Neoplásica , Estadificación de Neoplasias , Pronóstico , Transducción de Señal/efectos de los fármacosRESUMEN
We found that the human colon cancer cell line SW480 consists of two distinct subpopulations which we have designated E-type (epithelial) and R-type (round). Pure cultures of each type were obtained by subcloning, and both have maintained their characteristic phenotypes for at least 1 year (40 passages). E-type cells are the major (> 98%) type in the parental SW480 cell line. They form flat epithelial-like colonies. In contrast, R-type cells, which constitute a minor fraction (< 2%) of the parental cell line, have a rounded shape and grow in clusters of piled-up cells. Compared to E-type cells or the parental SW480 cells, isolated R-type cells display decreased doubling time, loss of contact inhibition, less adhesiveness to culture plates, higher anchorage-independent growth in soft agar, and a much more aneuploid karyotype. When injected s.c. into nude mice, R-type cells produce much larger tumors within the same period of time than E-type cells, and the tumors are less differentiated than those produced by the E-type cells. Cell fusion experiments between R-type and E-type cells revealed that the R-type phenotype is dominant, and the results suggest that this is due to one or a few genetic changes. Taken together, these findings suggest that the R-type cells represent a more malignant variant of the E-type cells. They may be useful, therefore, for studying mechanisms involved in tumor progression.
Asunto(s)
Neoplasias del Colon/patología , Animales , División Celular , Fusión Celular , Aberraciones Cromosómicas , Células Clonales , Neoplasias del Colon/genética , Femenino , Citometría de Flujo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Desnudos , Células Tumorales CultivadasRESUMEN
The enzyme ornithine decarboxylase (ODC) has been implicated in the control of cell growth, differentiation and tumor promotion. To further elucidate its precise role a murine ODC cDNA was inserted into the retrovirus-derived vector pMV7 and retrovirus-like particles were used to infect NIH3T3 and rat 6(R6) fibroblasts. Derivatives were obtained that stably express a 5-40 fold increase in ODC enzyme activity. Despite these high levels of enzyme activity the cells retained a normal morphology and displayed no major changes in growth properties in monolayer culture or in agar suspension. On the other hand, R6 cells that expressed high levels of ODC displayed a marked increase in susceptibility to morphologic transformation by an activated c-H-ras oncogene. These results provide the first evidence that ODC can cooperate with an activated oncogene in the process of cell transformation. Although the mechanism is not known, these findings may be relevant to the multistage carcinogenic process.
Asunto(s)
División Celular , Transformación Celular Neoplásica , Genes ras , Ornitina Descarboxilasa/genética , Animales , Línea Celular , Células Clonales , Ratones , Ornitina Descarboxilasa/metabolismo , Plásmidos , ARN/genética , ARN/aislamiento & purificación , Ratas , TransfecciónRESUMEN
To determine the status of chromosome 10q23 in primary breast carcinomas, in situ and invasive carcinomas were analysed for allelic loss using microsatellite markers spanning the 10q23 region. No LOH was seen in pure intraductal carcinomas (0/20 cases). On the other hand, LOH was observed in 40% (17/42) of invasive carcinomas (P = 0.0005). Interestingly, in situ lesions found in invasive tumors displayed LOH. Allelic loss was also significantly associated with loss of the estrogen receptor (P = 0.011). Thus, loss of the 10q23 is strongly associated with tumor progression.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/fisiopatología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/fisiopatología , Cromosomas Humanos Par 10 , Pérdida de Heterocigocidad , Monoéster Fosfórico Hidrolasas , Proteínas Supresoras de Tumor , Neoplasias de la Mama/patología , Carcinoma in Situ , Carcinoma Ductal de Mama/patología , Progresión de la Enfermedad , Femenino , Humanos , Mutación , Invasividad Neoplásica , Fosfohidrolasa PTEN , Proteínas Tirosina Fosfatasas/genéticaRESUMEN
Neoplastic progression in Barrett's esophagus is a multi-step process in which the metaplastic columnar epithelium sequentially evolves through a metaplasia-dysplasia-carcinoma sequence. The expression and DNA copy number of key cell cycle regulatory genes in paired normal and Barrett's esophagus samples was evaluated. Protein levels were evaluated in 60 formalin-fixed, paraffin-embedded human tissues by immunohistochemistry. DNA copy number from 20 fresh tissue pairs was analysed by Southern blot analysis. All normal mucosal samples expressed the p27(kip1) protein, but did not display appreciable nuclear staining for p16(kip4), p21(cip1) or cyclins D1 and E. Barrett's metaplastic specimens displayed increased expression levels of p16(kip4) (74%), p21(cip1) (89%) and cyclins D1 (43%) and E (37%). p27 protein was absent in three cases. There was a significant correlation between the expression of p16(kip4) and cyclin E, and p21(cip1) and p27(kip4) with cyclin D1. DNA analysis did not reveal any amplification or deletion of these genes. Acid suppression, however, was associated with significantly lower expression levels of key cell cycle proteins. Increased expression of key cell cycle regulatory genes appears to occur early in the neoplastic progression associated with Barrett's esophagus. Treatment with proton pump inhibitors appears to alter this increased expression.
Asunto(s)
Esófago de Barrett/genética , Esófago de Barrett/patología , Ciclo Celular/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Inhibidores de la Bomba de Protones , Adulto , Anciano , Anciano de 80 o más Años , Antiulcerosos/farmacología , Esófago de Barrett/tratamiento farmacológico , Ciclina D1/genética , Ciclina E/genética , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Inhibidor p21 de las Quinasas Dependientes de la Ciclina , Ciclinas/genética , ADN de Neoplasias/análisis , ADN de Neoplasias/genética , Inhibidores Enzimáticos/uso terapéutico , Femenino , Dosificación de Gen , Genes Supresores de Tumor , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Antígeno Nuclear de Célula en Proliferación/genética , Bombas de Protones/metabolismoRESUMEN
Cdc25 phosphatases activate cyclin-dependent kinases (Cdks) by dephosphorylating critical phospho-tyrosine and phospho-threonine residues on these proteins. Several types of studies indicate that Cdc25s can enhance cell proliferation and oncogenesis. Furthermore, overexpression of Cdc25A and/or B have been detected in several types of primary human cancers, including breast cancers. To further assess the oncogenic capacity of Cdc25B in vivo, we have generated transgenic mice that overexpress Cdc25B in the mammary epithelium, driven by the MMTV - LTR promoter. Although these mice are grossly normal for up to 18 months, the ectopic expression of Cdc25B in their mammary glands increases the susceptibility of these mice to induction of mammary tumors by the carcinogen 9,10-dimethyl-1, 2-benzanthracene (DMBA).
Asunto(s)
9,10-Dimetil-1,2-benzantraceno/toxicidad , Carcinógenos/toxicidad , Proteínas de Ciclo Celular/genética , Isoenzimas/genética , Neoplasias Mamarias Experimentales/inducido químicamente , Virus del Tumor Mamario del Ratón/genética , Fosfoproteínas Fosfatasas/genética , Secuencias Repetidas Terminales , Animales , Proteínas de Ciclo Celular/biosíntesis , Proteínas de Ciclo Celular/fisiología , Células Epiteliales/enzimología , Regulación Viral de la Expresión Génica , Predisposición Genética a la Enfermedad , Neoplasias Mamarias Experimentales/enzimología , Neoplasias Mamarias Experimentales/genética , Ratones , Ratones Endogámicos CBA , Ratones Transgénicos , Fosfoproteínas Fosfatasas/biosíntesis , Fosfoproteínas Fosfatasas/fisiología , Fosforilación , Procesamiento Proteico-Postraduccional , Proteínas Recombinantes de Fusión/biosíntesis , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/fisiología , Transgenes , Fosfatasas cdc25RESUMEN
To broaden the clinical applicability of peptide-based immunotherapy in breast cancer, there is a need to identify further tumor-associated peptide epitopes that are specific for HLA alleles, in addition to HLA-A2. The HLA-B44 haplotype is one of the most common HLA-B haplotypes, occurring in 10-20% of the population. We performed the structural characterization of HLA class I-bound self-peptides presented by a human breast cancer cell line with a HLA-A68, A32, B40, B44 haplotype, to identify potential tumor-specific antigens. Of 13 sequenced peptides, 1 peptide had the HLA-A68 peptide binding motif and 12 peptides had the HLA-B40, B44 peptide binding motif. One of the latter peptides, FEVRVCACPG, shared 100% homology to residues 270-279 of wild-type P53 protein. Our study, thus, provides direct evidence for the natural processing and presentation of p53 epitope 270-279 by HLA-B40, B44-bearing human breast tumor cells. Epitopes spanning this region of P53 may have potential use for immunotherapy in patients expressing HLA-A2 and -B44 supertypes.
Asunto(s)
Adenocarcinoma/inmunología , Presentación de Antígeno/inmunología , Neoplasias de la Mama/inmunología , Antígenos HLA-B/inmunología , Proteína p53 Supresora de Tumor/inmunología , Secuencia de Aminoácidos , Cromatografía Líquida de Alta Presión , Epítopos/inmunología , Femenino , Técnica del Anticuerpo Fluorescente Directa , Antígenos HLA-B/química , Haplotipos/inmunología , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunofenotipificación , Fragmentos de Péptidos/química , Fragmentos de Péptidos/inmunología , Análisis de Secuencia , Células Tumorales CultivadasRESUMEN
Protein complexes composed of cyclins and cyclin-dependent kinases control the orderly progression of mammalian cells through the cell cycle. The p27(Kip1) protein belongs to a family of cyclin-dependent kinase-inhibitory proteins that are negative regulators of cell cycle progression and have been proposed as candidate tumor suppressor genes. However, the p27(Kip1) gene is only rarely mutated in human primary breast carcinomas and breast cancer cell lines. To further address the role of p27(Kip1) in the development of human tumors, we determined by Western blot analysis the levels of expression of the p27(Kip1) protein in a series of human cancer cell lines and found that this protein is expressed at high levels in many of these cell lines, even during exponential growth. The levels of p27(Kip1) were significantly associated with the levels of cyclins D1 and E. In contrast to the high level of p27(Kip1) in breast cancer cell lines, three cell lines established from normal mammary epithelium expressed low levels of this protein. Cell synchronization studies demonstrated deregulation of the expression of p27(Kip1) throughout the cell cycle in two breast cancer cell lines but normal regulation in a normal mammary epithelial cell line. Immunohistochemical studies on p27(Kip1) expression in 52 primary human breast cancers indicated that this protein was also expressed at relatively high levels in 44% of the tumor samples, but it was barely detectable or undetectable in the remaining 56% of the samples. Additional studies are required to determine why some breast cancer cells express relatively high levels of p27(Kip1) despite its known role as an inhibitor of cell cycle progression.
Asunto(s)
Biomarcadores de Tumor/biosíntesis , Neoplasias de la Mama/genética , Proteínas de Ciclo Celular , Regulación Neoplásica de la Expresión Génica , Proteínas Asociadas a Microtúbulos/biosíntesis , Proteínas de Neoplasias/biosíntesis , Proteínas Supresoras de Tumor , Biomarcadores de Tumor/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Carcinoma in Situ/genética , Carcinoma in Situ/metabolismo , Carcinoma in Situ/patología , Carcinoma Ductal de Mama/genética , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Lobular/genética , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Ciclo Celular , División Celular , Línea Celular Transformada , Ciclina D1/biosíntesis , Ciclina D1/genética , Ciclina E/biosíntesis , Ciclina E/genética , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Femenino , Humanos , Proteínas Asociadas a Microtúbulos/genética , Proteínas de Neoplasias/genética , Células Tumorales CultivadasRESUMEN
This study was undertaken to explore whether the incidence of breast tumors that overexpress HER-2/neu protein product (HER-2/neu+) is more strongly associated with oral contraceptives (OCs) and other factors than is the incidence of tumors that do not (HER-2/neu-). In a population-based sample of women <45 years, 42.9% (159 of 371) of in situ and invasive breast cancer cases were HER-2/neu+ as assessed by immunohistochemistry in archived tissue. Polytomous logistic regression was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) for HER-2/neu+ and HER-2/neu-breast cancer, as compared with 462 population-based controls, in relation to OCs and other factors. The ratio of the ORs (HER-2/neu+ versus HER-2/neu-tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted ratio of ORs, 1.29; 95% CI, 0.83-2.00). Among early pill users (< or =18 years of age) heterogeneity was apparent (2.39; 95% CI, 1.08-5.30), which was attenuated in a multivariate model (1.99; 95% CI, 0.87-4.54); among cases with estrogen receptor-negative tumors, heterogeneity increased to 5-fold. For other risk factors, there was no marked heterogeneity between + and - tumors for HER-2/neu. In summary, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the odds ratio for +tumors twice that for -tumors.
PIP: This population-based study was undertaken to address the hypothesis that the incidence of breast tumor with a high HER-2/neu+ protein product was associated with oral contraceptive (OC) use and other risk factors compared with HER-2/neu- tumors. The study was conducted through the collection of archived paraffin-embedded tissue blocks, laboratory evaluation and combined laboratory results with risk factor information. About 159 of 371 (42.9%) in-situ and invasive breast cancer cases showed overexpression of HER-2/neu+ during immunohistochemistry of archived tissue. During the statistical analysis using a polytomous logistic regression, odds ratio (OR) was calculated and 95% confidence interval (CI) for HER-2/neu+ breast cancer and HER-2/neu- breast cancer compared with 401 controls regarding OC use and other risk factors. The OR (HER-2/neu+ vs. HER-2/neu- tumors) was used as an indicator of heterogeneity in risk. There was little heterogeneity in risk for OC use of 6 months or more by HER-2/neu status (age-adjusted OR, 1.29; 95% CI, 0.83-2.00). In early pill users, heterogeneity by HER-2/neu status was apparent (2.39; 95% CI, 1.08-5.30). A 5-fold increase in heterogeneity risk was noted among women with estrogen receptor (ER) negative tumors. In conclusion, the incidence of breast cancer among younger women in relation to OC use at an early age varied with HER-2/neu status, with the OR for positive tumors being twice that for negative tumors.
Asunto(s)
Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/etiología , Anticonceptivos Orales/efectos adversos , Neoplasias Hormono-Dependientes/epidemiología , Neoplasias Hormono-Dependientes/etiología , Receptor ErbB-2/metabolismo , Adulto , Distribución por Edad , Estudios de Casos y Controles , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Incidencia , Modelos Logísticos , New Jersey/epidemiología , Oportunidad Relativa , Receptor ErbB-2/genética , Factores de RiesgoRESUMEN
p53 mutations may be a fingerprint for cigarette smoking and other environmental carcinogens, including breast carcinogens. This study was undertaken to explore whether p53 mutations are associated with environmental or other suspected or established risk factors for breast cancer. p53 protein detection by immunohistochemistry (which is more easily quantified in large epidemiological studies than are mutations, and are highly correlated with them) was determined for 378 patients from a case-control study of breast cancer. In this population-based sample of women under the age of 45 years, 44.4% (168/378) of the cases had p53 protein detected by immunohistochemistry (p53+). Polytomous logistic regression was used to calculate the odds ratios (ORs) for p53+ and p53- breast cancer, as compared with the controls, in relation to cigarette smoking and other factors. The ratio of the ORs was used as an indicator of heterogeneity in risk for p53+ versus p53- cancer. The ratio of the ORs in a multivariate model was substantially elevated among women with a greater than high school education [2.39; 95% confidence interval (CI), 1.43-4.00], current cigarette smokers (1.96; 95% CI, 1.10-3.52), and users of electric blankets, water beds, or mattresses (1.78; 95% CI, 1.11-2.86). Nonsignificant heterogeneity was noted for family history of breast cancer and ethnicity but not for other known or suspected risk factors. Coupled with the strong biological plausibility of the association, our data support the hypothesis that in breast cancer, as with other tumors, p53 protein immunohistochemical detection may be associated with exposure to environmental carcinogens such as cigarette smoking.
Asunto(s)
Neoplasias de la Mama/etiología , Regulación Neoplásica de la Expresión Génica , Genes p53/genética , Fumar/efectos adversos , Proteína p53 Supresora de Tumor/genética , Adulto , Ropa de Cama y Ropa Blanca , Lechos , Neoplasias de la Mama/genética , Carcinógenos/efectos adversos , Estudios de Casos y Controles , Intervalos de Confianza , Escolaridad , Estudios Epidemiológicos , Etnicidad , Femenino , Humanos , Inmunohistoquímica , Modelos Logísticos , Análisis Multivariante , Mutación/genética , Oportunidad Relativa , Vigilancia de la Población , Historia Reproductiva , Factores de RiesgoRESUMEN
Small studies have examined, with conflicting results, whether breast cancer risk is increased among women exposed to high levels of chlorinated hydrocarbons, as measured in breast fat tissue or peripheral blood collected prior to treatment (pretreatment blood). For a population-based, case-control study, collection of pretreatment blood is a labor-intensive effort. An alternative is to collect blood from cases at interview, as is done for controls, after breast cancer treatment has commenced (posttreatment blood). It is unknown whether treatment affects blood levels of the organochlorines 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene (DDE) or polychlorinated biphenyls (PCBs). The purpose of this study was to determine whether pretreatment versus posttreatment blood samples yielded significantly different estimates of cumulative exposure to DDE and PCBs among newly diagnosed breast cancer patients. Two-ml blood samples were collected prior to and after treatment for breast cancer from 22 nonfasting women, ages 45-87 years, newly diagnosed with invasive disease. Treatment was defined as major surgery (mastectomy or node removal), radiation, hormones (tamoxifen), or chemotherapy. Pretreatment and posttreatment blood samples were assayed for DDE and PCBs in blinded, matched pairs. The reported concentrations (volume basis) were adjusted for estimated total plasma lipids. For DDE, mean differences in unadjusted [0.99 ng/ml; 95% confidence interval (CI), -0.36 to 2.34 ng/ml] and lipid-adjusted (0.05 microgram/g lipid; 95% CI, -0.04 to 0.13 microgram/g lipid) levels were small. For PCBs, the unadjusted (0.68 ng/ml; 95% CI, 0.05 to 1.30 ng/ml) and adjusted (0.070 microgram/g lipid; 95% CI, -0.009 to 0.149 microgram/g lipid) mean differences were of borderline statistical significance. The mean percent change in lipid-adjusted organochlorine levels did not vary substantially between treatment groups, except for those patients receiving chemotherapy [n = 5; 15.8% (DDE), 29.4% (PCBs)]. Adjusted mean differences also increased with increasing time between the pretreatment and posttreatment blood draws. In multiple regression models that included treatment, age, race, stage, and time between blood draws, only chemotherapy appeared to predict the percent change in adjusted pretreatment and posttreatment levels of DDE or PCBs (P = 0.10 and 0.06, respectively). Posttreatment blood samples drawn within 3 months of pretreatment samples, with the exception of those drawn after the commencement of chemotherapy, provide similar measures of DDE body burden levels among breast cancer cases. The use of blood samples collected after treatment, rather than before treatment, for characterizing PCB levels may lead to misclassification of exposure.
Asunto(s)
Neoplasias de la Mama/sangre , Hidrocarburos Clorados/farmacocinética , Anciano , Anciano de 80 o más Años , Mama/metabolismo , Neoplasias de la Mama/terapia , Estudios de Casos y Controles , Terapia Combinada , Diclorodifenil Dicloroetileno/farmacocinética , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Bifenilos Policlorados/farmacocinéticaRESUMEN
Tumors of the small bowel are quite rare for unknown reasons, although they resemble colorectal tumors in many respects. The purpose of this study was to determine whether abnormalities in the expression of several cell cycle control genes are of importance in small bowel tumorigenesis by comparing a series of samples of normal mucosa, adenomatous polyps, and adenocarcinomas. The levels of cyclin D1, cyclin E, p16, p21, p27, and p53 proteins were determined by immunohistochemistry in samples of normal small bowel (n = 16), small bowel adenomas (n = 20), and small bowel adenocarcinomas (n = 24). Normal small bowel mucosa expressed p27 protein, but not the other cell cycle-related proteins. About 20% of the tumors displayed a decrease in the expression of this protein. The most frequent alteration in the tumors was an increase in the p16 protein. Increased expression of p53 was associated with tumor progression because it was overexpressed in 45% of the adenomas and 65% of the adenocarcinomas (P<0.05). Advanced age and increased detection of cyclin D1 and p53 were associated with a decreased 3-year survival (P<0.05). Cell cycle abnormalities are early and important events in the multistep process of small bowel tumorigenesis, thus resembling colorectal carcinogenesis. As in colon cancer, deregulated expression of G1 proteins may perturb cell cycle control in benign adenomas of the small bowel and thereby enhance tumor progression. Increased expression of cell cycle inhibitors in tumors may serve as a defense mechanism for tumor progression.
Asunto(s)
Adenocarcinoma/patología , Pólipos Adenomatosos/patología , Proteínas de Ciclo Celular/análisis , Regulación Neoplásica de la Expresión Génica/genética , Neoplasias Intestinales/patología , Intestino Delgado , Proteínas Supresoras de Tumor , Adenocarcinoma/etiología , Adenocarcinoma/mortalidad , Pólipos Adenomatosos/etiología , Pólipos Adenomatosos/mortalidad , Adulto , Distribución por Edad , Anciano , Anciano de 80 o más Años , Estudios de Casos y Controles , Ciclina D1/análisis , Ciclina E/análisis , Inhibidor p16 de la Quinasa Dependiente de Ciclina/análisis , Inhibidor p27 de las Quinasas Dependientes de la Ciclina , Quinasas Ciclina-Dependientes/antagonistas & inhibidores , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Neoplasias Intestinales/etiología , Neoplasias Intestinales/mortalidad , Estilo de Vida , Masculino , Proteínas Asociadas a Microtúbulos/análisis , Persona de Mediana Edad , Proteínas Proto-Oncogénicas p21(ras)/análisis , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/análisisRESUMEN
Previous studies have found a 3-10-fold amplification and overexpression of the cyclin D1 gene in about 32% of human esophageal squamous cell carcinoma. The purpose of this study was to evaluate the prevalence of increased expression of the cyclin D1 protein in Barrett's esophagus. Using 69 formalin-fixed and paraffin-embedded human esophageal specimens, which had been removed endoscopically or obtained at surgery during 1993 and 1994, all immunohistochemical analyses were performed using an avidin-biotin complex immunoperoxidase technique. Increased nuclear expression of the cyclin D1 protein was noted in 32 of 69 samples (46%; 44% of the samples from males and 50% of the samples from females). Positive nuclear staining for the cyclin D1 protein in Barrett's disease with intestinal metaplasia was found in 38% of the male cases and 25% of the female cases, whereas in gastric metaplasia it was positive in 33% of men and 48% of women. Nuclear accumulation of the cyclin D1 protein was also found in both dysplastic and nondysplastic lesions, and it was not associated with sex, age, or cigarette or alcohol consumption. Samples from patients taking proton pump inhibitors tended to be less frequently positive (32%) for cyclin D1 nuclear staining when compared to patients taking H2 antagonists (45%) or antacids (55%). These studies suggest that increased expression of cyclin D1 is an early event in the tumorigenic process of esophageal adenocarcinomas and that the increased expression of this gene might predispose the epithelium to malignant transformation.
Asunto(s)
Adenocarcinoma/genética , Esófago de Barrett/genética , Carcinoma de Células Escamosas/genética , Ciclinas/genética , Neoplasias Esofágicas/genética , Proteínas Oncogénicas/genética , Adenocarcinoma/patología , Adulto , Anciano , Anciano de 80 o más Años , Esófago de Barrett/patología , Carcinoma de Células Escamosas/patología , Transformación Celular Neoplásica/genética , Transformación Celular Neoplásica/patología , Ciclina D1 , Neoplasias Esofágicas/patología , Esófago/patología , Femenino , Humanos , Técnicas para Inmunoenzimas , Masculino , Metaplasia , Persona de Mediana Edad , Factores de RiesgoRESUMEN
During the past two decades we have witnessed the identification of an expanding list of immunohistochemical and molecular markers linked to histopathologically defined subtypes of tumors. These markers offer new insights and approaches to the classification of tumors with important prognostic and/or therapeutic implications. We review the potentially diagnostic immunohistochemical and molecular markers of soft tissue tumors (STTs). The immunohistochemical markers reviewed include vimentin, cytokeratin, desmin, HHF35, S100, myoD1, alpha1-antitrypsin, vascular markers (factor VIII, CD31, CD34), MIC2, and others. The potentially diagnostic chromosomal translocations and associated genes identified in STT include Ewing's/PNET t(11;22)(q24;q12)(FLI1;EWS), t(21;22)(q22;q12)(ERG; EWS); t(7;22)(p22;q12)(ETV1;EWS); desmoplastic small round cell tumor t(11;22)(p13;q12)(WT1;EWS); extraskeletal myxoid chondrosarcoma t(9;22)(q22;q12) (TEC(CHN);EWS); malignant ectomesenchymoma t(11;22)(q24;q12)(FLI1;EWS); alveolar rhabdomyosarcoma t(2;13)(q35;q14)(PAX-3;FKHR); t(1;13) (p36;q14)(PAX-7;FKHR); myxoid and round cell liposarcoma t(12;16)(q13;p11)(CHOP;TLS(FUS)); synovial sarcoma t(X;18)(p11;q11)(SSX1&2;SYT), and others. The nature, utility, and limitations of these markers in diagnostic settings are explored.
Asunto(s)
Biomarcadores de Tumor , Sarcoma/genética , Sarcoma/metabolismo , Translocación Genética , Citodiagnóstico , Humanos , Inmunohistoquímica , Sarcoma/clasificación , Sarcoma/diagnóstico , Sarcoma/patologíaRESUMEN
Environmental carcinogens may play a role in the etiology of breast cancer, but the extent of their contribution is not yet defined. The aims of this study were to determine whether polycyclic aromatic hydrocarbon (PAH)-DNA adducts could be detected in stored paraffin blocks of breast tumor tissue (n=147) with an immunoperoxidase technique and whether they correlated with smoking history and/or mutant p53 protein expression. There was no significant difference in mean relative nuclear staining intensity in non-smokers (444+/-90, n=75), ever smokers (435+/-91, n=72), and current smokers (456+/-98, n=35). In either current or ever smokers, PAH-DNA adducts were non-significantly elevated in those with greater compared with lower exposure in relation to age at started smoking, years of smoking, cigarettes per day, and pack years. DNA damage levels were not elevated in tissues with compared with those without mutant p53 protein expression. These data demonstrate that immunohistochemical methods can be used to monitor DNA damage levels in archived breast tissues.
Asunto(s)
Neoplasias de la Mama/metabolismo , Aductos de ADN/metabolismo , Hidrocarburos Policíclicos Aromáticos/metabolismo , Fumar , Adulto , Factores de Edad , Análisis de Varianza , Neoplasias de la Mama/genética , Carcinógenos/metabolismo , Aductos de ADN/biosíntesis , Daño del ADN , Femenino , Genes p53/genética , Humanos , Inmunohistoquímica , Mutación , Proteína p53 Supresora de Tumor/metabolismoRESUMEN
Increased expression of the cyclin D1 gene frequently occurs in human squamous carcinomas of the esophagus. However, the expression of cyclin D1 has not been previously examined in detail in adenocarcinomas of the esophagus or stomach. Therefore, we examined, in parallel, the expression of cyclin D1 in both squamous and adenocarcinomas of the esophagus and in adenocarcinomas of the stomach. The level of expression of the cyclin D1 protein was assessed by immunohistochemistry in 39 esophageal and 34 gastric carcinomas and correlated with clinical and pathology parameters. Within the esophagus, 71% of the squamous carcinomas and 64% of the adenocarcinomas were positive for increased cyclin D1 nuclear staining. For adenocarcinomas of the stomach, the overall positive rate was 47%; in the gastric cardia, the rate was 44%, and in other regions of the stomach, it was 50%. In esophageal and gastric adenocarcinomas of the intestinal type, increased expression of cyclin D1 was seen in 70% of the samples, whereas with the diffuse type only 13% were positive (P < .01). Tumors from patients older than the median age of 67 years were more frequently positive than tumors from patients younger than 67 years (74% v 42%, respectively) (P < .01). Positive staining was also seen more frequently in well and moderately differentiated tumors than in poorly differentiated tumors (74% v 49%, respectively) (P < .05). Cytoplasmic staining for cyclin D1 was noted in 22% of the tumors, of various types. Therefore, increased expression of cyclin D1 frequently occurs in both adenocarcinomas and squamous carcinomas of the esophagus, and in adenocarcinomas of the stomach. The increased expression in adenocarcinomas is especially frequent in the intestinal-type lesions.
Asunto(s)
Adenocarcinoma/metabolismo , Carcinoma de Células Escamosas/metabolismo , Ciclina D1/biosíntesis , Neoplasias Esofágicas/metabolismo , Neoplasias Gástricas/metabolismo , Adenocarcinoma/patología , Adulto , Anciano , Carcinoma de Células Escamosas/patología , Neoplasias Esofágicas/patología , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/patologíaRESUMEN
The ability to identify individuals who are predisposed to specific malignant tumors is a promising molecular diagnostic by-product of over two decades of intensive research into the genetic pathogenesis of human cancer. Approximately 2% of Ashkenazi Jews carry recurrent germline mutations in either the BRCA1 or BRCA2 genes that may predispose these individuals to the development of breast and ovarian cancer. We have developed a nonisotopic method, based on the formation of heteroduplexes between polymerase chain reaction (PCR) amplified wild-type and mutant alleles, which can be used to identify the BRCA1 185delAG and the BRCA2 6174delT mutations. The same assay can also be used to verify the loss of heterozygosity in a tumor sample arising in an individual with a germline mutation. The four steps described in this report (PCR amplification, heteroduplex formation, acrylamide gel electrophoresis, and ethidium bromide staining/UV-fluorescence photography) can be readily and reproducibly performed in the course of a single day, making this a useful method for the routine identification of these mutations.