RESUMO
BACKGROUND: We investigated the outcomes of postmenopausal women with hormone receptor-positive, early breast cancer with special histotypes (mucinous, tubular, or cribriform) enrolled in the monotherapy cohort of the BIG 1-98 trial. PATIENTS AND METHODS: The intention-to-treat BIG 1-98 monotherapy cohort (5 years of therapy with tamoxifen or letrozole) included 4922 women, of whom 4091 had central pathology review. Histotype groups were defined as: mucinous (N = 100), tubular/cribriform (N = 83), ductal (N = 3257), and other (N = 651). Of 183 women with either mucinous or tubular/cribriform tumors, 96 were randomly assigned to letrozole and 87 to tamoxifen. Outcomes assessed were disease-free survival (DFS), overall survival (OS), breast cancer-free interval (BCFI), and distant recurrence-free interval (DRFI). Median follow-up in the analytic cohort was 8.1 years. RESULTS: Women with tubular/cribriform breast cancer had the best outcomes for all end points compared with the other three histotypes, and had less breast cancer recurrence (97.5% 5-year BCFI) than those with mucinous (93.5%), ductal (88.9%), or other (89.9%) histotypes. Patients with mucinous or tubular/cribriform carcinoma had better DRFI (5-year rates 97.8% and 98.8%, respectively) than those with ductal (90.9%) or other (92.1%) carcinomas. Within the subgroup of women with special histotypes, we observed a nonsignificant increase in the hazard of breast cancer recurrence with letrozole [hazard (letrozole versus tamoxifen): 3.31, 95% confidence interval 0.94-11.7; P = 0.06]. CONCLUSIONS: Women with mucinous or tubular/cribriform breast cancer have better outcomes than those with other histotypes, although the observation is based on a limited number of events. In postmenopausal women with these histotypes, the magnitude of the letrozole advantage compared with tamoxifen may not be as large in patients with mucinous or tubular/cribriform disease. CLINICALTRIALSGOV: NCT00004205.
Assuntos
Antineoplásicos Hormonais/administração & dosagem , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Nitrilas/administração & dosagem , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal de Mama/diagnóstico , Carcinoma Ductal de Mama/tratamento farmacológico , Quimioterapia Adjuvante , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Seguimentos , Humanos , Letrozol , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/tratamento farmacológico , Resultado do TratamentoRESUMO
Cell-matrix interactions control outgrowth of mammary epithelium during puberty and pregnancy. We demonstrate here that the glycoprotein fibulin-2 (FBLN2) is strongly associated with pubertal and early pregnant mouse mammary epithelial outgrowth. FBLN2 was specifically localized to the cap cells of the terminal end buds during puberty and to myoepithelial cells during very early pregnancy (days 2-3) even before morphological changes to the epithelium become microscopically visible, but was down-regulated thereafter. Exposure to exogenous oestrogen (E2) or E2 plus progesterone (P) increased Fbln2 mRNA expression in the pubertal gland, indicating hormonal control. FBLN2 was co-expressed and co-localised with the proteoglycan versican (VCAN) and co-localised with laminin (LN), while over-expression of FBLN2 in HC-11 cells increased cell adhesion to several extracellular matrix proteins including LN and fibronectin, but not collagens. Mammary glands from Fbln2 knockout mice showed no obvious phenotype but increased fibulin-1 (FBLN1) staining was detected, suggesting a compensatory mechanism by other fibulin family members. We hypothesise that similar to embryonic aortic smooth muscle development, FBLN2 and VCAN expression alters the cell-matrix interaction to allow mammary ductal outgrowth and development during puberty and to enable epithelial budding during pregnancy.
Assuntos
Proteínas de Ligação ao Cálcio/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Matriz Extracelular/metabolismo , Glândulas Mamárias Animais/metabolismo , Animais , Proteínas de Ligação ao Cálcio/deficiência , Proteínas de Ligação ao Cálcio/genética , Movimento Celular/efeitos dos fármacos , Células Cultivadas , Estrogênios/farmacologia , Proteínas da Matriz Extracelular/deficiência , Proteínas da Matriz Extracelular/genética , Feminino , Fibronectinas/metabolismo , Laminina/análise , Laminina/metabolismo , Masculino , Glândulas Mamárias Animais/citologia , Glândulas Mamárias Animais/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Gravidez , Progesterona/farmacologia , RNA Mensageiro/metabolismo , Versicanas/análise , Versicanas/metabolismoRESUMO
Human synovial sarcomas contain a recurrent and specific chromosomal translocation t(X;18)(p11.2;q11.2). By screening a synovial sarcoma cDNA library with a yeast artificial chromosome spanning the X chromosome breakpoint, we have identified a hybrid transcript that contains 5' sequences (designated SYT) mapping to chromosome 18 and 3' sequences (designated SSX) mapping to chromosome X. An SYT probe detected genomic rearrangements in 10/13 synovial sarcomas. Sequencing of cDNA clones shows that the normal SYT gene encodes a protein rich in glutamine, proline and glycine, and indicates that in synovial sarcoma rearrangement of the SYT gene results in the formation of an SYT-SSX fusion protein. Both SYT and SSX failed to exhibit significant homology to known gene sequences.
Assuntos
Cromossomos Humanos Par 18 , Sarcoma Sinovial/genética , Translocação Genética , Cromossomo X , Sequência de Aminoácidos , Sequência de Bases , Primers do DNA/genética , DNA Complementar/genética , DNA de Neoplasias/genética , Rearranjo Gênico , Humanos , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , RNA Neoplásico/genética , Mapeamento por Restrição , Células Tumorais CultivadasRESUMO
The allele sizes of polymorphic microsatellite repeats in DNA from human cancers were compared to normal DNA from the same patients. In 16 out of 196 paired samples (8%), we found evidence of an extra allele of a different size in the tumour which was not present in the normal DNA. Sequence analysis confirmed that the extra allele originates from the appropriate locus and that the size change is attributable to alteration in the number of repeat units. This form of instability was more common in tri- and tetranucleotide repeats than in dinucleotide repeats. In any single tumour sample only one repeat in the set examined was abnormal, the remainder showing identical patterns in normal and tumour DNA or evidence of allele loss. The pattern of instability in diverse types of cancer differs from that reported in colorectal neoplasms.
Assuntos
DNA Satélite/genética , Neoplasias/genética , Polimorfismo Genético , Sequências Repetitivas de Ácido Nucleico/genética , Alelos , Sequência de Bases , Neoplasias Encefálicas/genética , Neoplasias da Mama/genética , DNA de Neoplasias/genética , Feminino , Humanos , Masculino , Dados de Sequência Molecular , Distrofia Miotônica/genética , Oligodesoxirribonucleotídeos , Neoplasias Ovarianas/genética , Sarcoma/genética , Análise de Sequência de DNARESUMO
BACKGROUND: The benefit of adjuvant chemotherapy in postmenopausal patients with estrogen receptor (ER)-positive lymph node-negative breast cancer is being reassessed. PATIENTS AND METHODS: After stratification by ER status, 1669 postmenopausal patients with operable lymph node-negative breast cancer were randomly assigned to three 28-day courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy followed by tamoxifen for 57 months (CMFâtamoxifen) or to tamoxifen alone for 5 years. RESULTS: ERs were positive in 81% of tumors. At a median follow-up of 13.1 years, patients with ER-positive breast cancers did not benefit from CMF [13-year disease-free survival (DFS) 64% CMFâtamoxifen, 66% tamoxifen; P = 0.99], whereas CMF substantially improved the prognosis of patients with ER-negative breast cancer (13-year DFS 73% versus 57%, P = 0.001). Similarly, breast cancer-free interval (BCFI) was identical in the ER-positive cohort but significantly improved by chemotherapy in the ER-negative cohort (13-year BCFI 80% versus 63%, P = 0.001). CMF had no influence on second nonbreast malignancies or deaths from other causes. CONCLUSION: CMF is not beneficial in postmenopausal patients with node-negative ER-positive breast cancer but is highly effective within the ER-negative cohort. In the future, other markers of chemotherapy response may define a subset of patients with ER-positive tumors who may benefit from adjuvant chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/metabolismo , Receptores de Estrogênio/biossíntese , Idoso , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metástase Linfática , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Tamoxifeno/administração & dosagemRESUMO
BACKGROUND: The International Breast Cancer Study Group Trial VIII compared long-term efficacy of endocrine therapy (goserelin), chemotherapy [cyclophosphamide, methotrexate and fluorouracil (CMF)], and chemoendocrine therapy (CMF followed by goserelin) for pre/perimenopausal women with lymph-node-negative breast cancer. PATIENTS AND METHODS: From 1990 to 1999, 1063 patients were randomized to receive (i) goserelin for 24 months (n = 346), (ii) six courses of 'classical' CMF (cyclophosphamide, methotrexate, 5-fluorouracil) chemotherapy (n = 360), or (iii) six courses of CMF plus 18 months goserelin (CMFâ goserelin; n = 357). Tumors were classified as estrogen receptor (ER) negative (19%), ER positive (80%), or ER unknown (1%); 19% of patients were younger than 40. Median follow-up was 12.1 years. RESULTS: For the ER-positive cohort, sequential therapy provided a statistically significant benefit in disease-free survival (DFS) (12-year DFS = 77%) compared with CMF alone (69%) and goserelin alone (68%) (P = 0.04 for each comparison), due largely to the effect in younger patients. Patients with ER-negative tumors whose treatment included CMF had similar DFS (12-year DFS CMF = 67%; 12-year DFS CMFâ goserelin = 69%) compared with goserelin alone (12-year DFS = 61%, P= NS). CONCLUSIONS: For pre/perimenopausal women with lymph-node-negative ER-positive breast cancer, CMF followed by goserelin improved DFS in comparison with either modality alone. The improvement was the most pronounced in those aged below 40, suggesting an endocrine effect of prolonged CMF-induced amenorrhea.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Adulto , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Quimioterapia Adjuvante , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Gosserrelina/administração & dosagem , Humanos , Linfonodos/patologia , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Pré-Menopausa , Receptores de Estrogênio/biossínteseRESUMO
BACKGROUND: On average, aromatase inhibitors are better than tamoxifen when used as initial or sequential therapy for postmenopausal women with endocrine-responsive early breast cancer. Because there may be contraindications to their use based on side-effects or cost, we investigated subgroups in which aromatase inhibitors may be more or less important. PATIENTS AND METHODS: Breast International Group 1-98 trial randomized 6182 women among four groups comparing letrozole and tamoxifen with sequences of each agent; 5177 (84%) had centrally confirmed estrogen receptor (ER) positivity. We assessed whether centrally determined ER, progesterone receptor (PgR), human epidermal growth factor receptor 2, and Ki-67 labeling index, alone or in combination with other prognostic features, predicted the magnitude of letrozole effectiveness compared with either sequence or tamoxifen monotherapy. RESULTS: Individually, none of the markers significantly predicted differential treatment effects. Subpopulation treatment effect pattern plot analysis of a composite measure of prognostic risk revealed three patterns. Estimated 5-year disease-free survival for letrozole monotherapy, letrozoleâtamoxifen, tamoxifenâletrozole, and tamoxifen monotherapy were 96%, 94%, 93%, and 94%, respectively, for patients at lowest risk; 90%, 91%, 93%, and 86%, respectively, for patients at intermediate risk; and 80%, 76%, 74%, and 69%, respectively, for patients at highest risk. CONCLUSION: A composite measure of risk informs treatment selection better than individual biomarkers and supports the choice of 5 years of letrozole for patients at highest risk for recurrence.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Inibidores da Aromatase/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Idoso , Neoplasias da Mama/enzimologia , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Método Duplo-Cego , Esquema de Medicação , Receptores ErbB/biossíntese , Feminino , Humanos , Antígeno Ki-67/biossíntese , Letrozol , Pessoa de Meia-Idade , Nitrilas/administração & dosagem , Prognóstico , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Tamoxifeno/administração & dosagem , Triazóis/administração & dosagemRESUMO
We previously showed that offspring of rat dams receiving a protein-restricted (low protein) diet throughout pregnancy and lactation develop mammary tumors more quickly. Rapid post-weaning mammary growth and mammary tissue overexpression of insulin receptor, insulin-like growth factor-1 receptor (IGF-1R), estrogen receptor isoform alpha and v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ERBB2), correlated with this risk. The objectives of this study were therefore (i) to identify underlying mechanisms of increased risk through candidate and global approaches; (ii) to determine if excessive calorie intake further increased risk and if so, (iii) to identify the molecular mechanisms mediating this. We provide evidence for transcriptional upregulation of IGF-1R by Sp1 in LP mammary tissue (P < 0.01). Cell cycle control and DNA damage repair gene cyclin-dependent kinase inhibitor 1A (CDKN1A) (p21waf1) was also upregulated (P < 0.05) as was transcription factor nuclear factor of kappa light polypeptide gene enhancer in B-cell (P < 0.05) and adhesion gene CDH1 (P < 0.05). Invasion and metastasis markers matrix metalloproteinase 9 and serpin peptidase inhibitor, clade E, member 1 (SERPIN1) were upregulated (both P < 0.05), whereas metastasis suppressor gene NME1 was downregulated (P < 0.01). Feeding a highly palatable diet (HPD) to increase calorie intake from puberty, additively and independently increased early mammary tumor risk, which correlated with increased serum insulin and triglyceride concentrations (P < 0.05). PTEN gene expression was reduced both by early protein restriction (P < 0.05) and HPD (P < 0.01), which may induce Akt in cell survival pathways. Progesterone receptor and ERBB2 (both P < 0.05) expression increased as an effect of an interaction between maternal diet and adult nutrition, with subsequent downstream activation of the mitogen-activated protein kinase pathway. We conclude that poor early growth and excessive calorie intake exert independent and additive effects on mitogenic growth factor signaling to influence mammary tumor susceptibility.
Assuntos
Ingestão de Energia , Transtornos do Crescimento/complicações , Neoplasias Mamárias Animais/etiologia , Transdução de Sinais , Animais , Peso Corporal , Suscetibilidade a Doenças , MAP Quinases Reguladas por Sinal Extracelular/metabolismo , Feminino , Perfilação da Expressão Gênica , Glândulas Mamárias Animais/química , Glândulas Mamárias Animais/metabolismo , Ratos , Ratos Wistar , Receptor ErbB-2/genética , Receptor ErbB-2/fisiologia , Receptor IGF Tipo 1/análise , Receptor IGF Tipo 1/genética , Fator de Transcrição Sp1/análise , Fator de Transcrição Sp1/genéticaRESUMO
BACKGROUND: Peritumoral vascular invasion (PVI) may assist in assigning optimal adjuvant systemic therapy for women with early breast cancer. PATIENTS AND METHODS: Patients participated in two International Breast Cancer Study Group randomized trials testing chemoendocrine adjuvant therapies in premenopausal (trial VIII) or postmenopausal (trial IX) node-negative breast cancer. PVI was assessed by institutional pathologists and/or central review on hematoxylin-eosin-stained slides in 99% of patients (analysis cohort 2754 patients, median follow-up >9 years). RESULTS: PVI, present in 23% of the tumors, was associated with higher grade tumors and larger tumor size (trial IX only). Presence of PVI increased locoregional and distant recurrence and was significantly associated with poorer disease-free survival. The adverse prognostic impact of PVI in trial VIII was limited to premenopausal patients with endocrine-responsive tumors randomized to therapies not containing goserelin, and conversely the beneficial effect of goserelin was limited to patients whose tumors showed PVI. In trial IX, all patients received tamoxifen: the adverse prognostic impact of PVI was limited to patients with receptor-negative tumors regardless of chemotherapy. CONCLUSION: Adequate endocrine adjuvant therapy appears to abrogate the adverse impact of PVI in node-negative disease, while PVI may identify patients who will benefit particularly from adjuvant therapy.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Hormonais/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/irrigação sanguínea , Neoplasias da Mama/patologia , Quimioterapia Adjuvante/métodos , Ciclofosfamida/uso terapêutico , Progressão da Doença , Feminino , Fluoruracila/uso terapêutico , Gosserrelina/uso terapêutico , Humanos , Menopausa/fisiologia , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Invasividade Neoplásica , Neovascularização Patológica/diagnóstico , Valor Preditivo dos Testes , Prognóstico , Resultado do TratamentoRESUMO
BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.
Assuntos
Antineoplásicos Hormonais/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais/análise , Neoplasias da Mama/química , Neoplasias da Mama/tratamento farmacológico , Antígeno Nuclear de Célula em Proliferação/análise , Proteínas Quinases Associadas a Fase S/análise , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/patologia , Ciclofosfamida/administração & dosagem , Intervalo Livre de Doença , Feminino , Fluoruracila/administração & dosagem , Gosserrelina/administração & dosagem , Humanos , Imuno-Histoquímica , Metotrexato/administração & dosagem , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Tamoxifeno/administração & dosagem , Resultado do TratamentoRESUMO
BACKGROUND: Extracapsular tumor spread (ECS) has been identified as a possible risk factor for breast cancer recurrence, but controversy exists regarding its role in decision making for regional radiotherapy. This study evaluates ECS as a predictor of local, axillary, and supraclavicular recurrence. PATIENTS AND METHODS: International Breast Cancer Study Group Trial VI accrued 1475 eligible pre- and perimenopausal women with node-positive breast cancer who were randomly assigned to receive three to nine courses of classical combination chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. ECS status was determined retrospectively in 933 patients based on review of pathology reports. Cumulative incidence and hazard ratios (HRs) were estimated using methods for competing risks analysis. Adjustment factors included treatment group and baseline patient and tumor characteristics. The median follow-up was 14 years. RESULTS: In univariable analysis, ECS was significantly associated with supraclavicular recurrence (HR = 1.96; 95% confidence interval 1.23-3.13; P = 0.005). HRs for local and axillary recurrence were 1.38 (P = 0.06) and 1.81 (P = 0.11), respectively. Following adjustment for number of lymph node metastases and other baseline prognostic factors, ECS was not significantly associated with any of the three recurrence types studied. CONCLUSIONS: Our results indicate that the decision for additional regional radiotherapy should not be based solely on the presence of ECS.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Recidiva Local de Neoplasia/patologia , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/radioterapia , Terapia Combinada , Ciclofosfamida/administração & dosagem , Feminino , Fluoruracila/administração & dosagem , Seguimentos , Humanos , Metástase Linfática , Metotrexato/administração & dosagem , Estadiamento de Neoplasias , Pré-Menopausa , Estudos Retrospectivos , Resultado do TratamentoRESUMO
The metastasizing rat mammary cell strain from the Ludwig Institute for Cancer Research (London Branch) which was originally developed from a benign rat mammary tumor induced by N-methyl-N-nitrosourea (CAS: 684-93-5), yielded single-cell-cloned lines of isometric epithelial cells [rat mammary (Rama) 600-Rama 621] and one line of elongated cells (Rama 622); the former had a higher estrogen receptor content than the latter. All the representative epithelial cell lines tested (Rama 600, 603, and 617) failed to convert to elongated, myoepithelial-like cells or droplet cell/doming, alveolar-like cells in vitro. All representative cell lines tested induced tumors in syngeneic F344/N rats and CBA nu/nu mice, but only the epithelial lines metastasized to lungs and local lymph nodes in rats and to lungs in nude mice. The involved lungs and lymph nodes contained mainly intravascular thrombi and deposits in the subcapsular sinus, respectively. Tumors and metastases from the representative epithelial cell lines contained acinar and glandular structures together with an elongated cellular component. The Rama 622 tumors contained mainly spindle cells. Antisera to rat milk fat globule membranes and human keratins stained some of the epithelial and elongated cells in the Rama 600 tumors; less staining was observed in the Rama 622 tumors. None of the tumor cells stained with antiserum to myosin. Anti-laminin serum delineated a fragmented basement membrane in glandular elements and stained weakly the cytoplasm of the more elongated tumor cells. Ultrastructural analysis confirmed the identity of epithelial cells in the Rama 600 tumors, but no well-differentiated myoepithelial cells were seen in either type of tumor. Since nonmetastasizing epithelial cells isolated directly from carcinogen-induced benign rat mammary tumors can differentiate to myoepithelial-like cells in vitro or when growing as tumors in animals, it is suggested that the development of the malignant phenotype is associated with a loss of this differentiating ability.
Assuntos
Neoplasias Mamárias Experimentais/patologia , 9,10-Dimetil-1,2-benzantraceno , Animais , Linhagem Celular , Feminino , Histocitoquímica , Queratinas/análise , Laminina/análise , Neoplasias Mamárias Experimentais/induzido quimicamente , Neoplasias Mamárias Experimentais/ultraestrutura , Metilnitrosoureia , Camundongos , Metástase Neoplásica , Transplante de Neoplasias , Ratos , Ratos Endogâmicos F344RESUMO
An immunohistological study in the human breast and the rodent breast (from inbred Ludwig/Wistar/Olac rats) was conducted with the use of a murine monoclonal antibody, which reacts with the common acute lymphoblastic antigen, a glycosylated polypeptide of a molecular weight of 100,000. The epitope, as recognized by this antibody, is expressed on myoepithelial cells of the normal human and rat breasts and was studied in the developing rodent mammary gland. Ultrastructural studies in the normal human breast clearly demonstrated the presence of the antigen on the lateral membrane of the myoepithelial cells with no staining of luminal cells, blood vessels, or stromal elements. The antigen survived prolonged enzymatic digestion of human breast tissue and could be demonstrated on myoepithelial cells in single-cell suspensions of human breast where it stained approximately 3-14% of the total cell population. The presence of this antigen on myoepithelial cells is discussed in the context of myoepithelial differentiation in the breast and the potential utility of the antibodies for cell separation.
Assuntos
Anticorpos Monoclonais , Antígenos de Neoplasias/análise , Neoplasias da Mama/patologia , Mama/citologia , Glândulas Mamárias Animais/citologia , Animais , Antígenos de Neoplasias/imunologia , Mama/imunologia , Neoplasias da Mama/imunologia , Diferenciação Celular , Células Epiteliais , Epitopos/análise , Feminino , Humanos , Glândulas Mamárias Animais/imunologia , Neprilisina , Gravidez , Ratos , Ratos EndogâmicosRESUMO
BACKGROUND: We have previously demonstrated that breast cancers associated with inherited BRCA1 and BRCA2 gene mutations differ from each other in their histopathologic appearances and that each of these types differs from breast cancers in patients unselected for family history (i.e., sporadic cancers). We have now conducted a more detailed examination of cytologic and architectural features of these tumors. METHODS: Specimens of tumor tissue (5-microm-thick sections) were examined independently by two pathologists, who were unaware of the case or control subject status, for the presence of cell mitosis, lymphocytic infiltration, continuous pushing margins, and solid sheets of cancer cells; cell nuclei, cell nucleoli, cell necrosis, and cell borders were also evaluated. The resulting data were combined with previously available information on tumor type and tumor grade and further evaluated by multifactorial analysis. All statistical tests are two-sided. RESULTS: Cancers associated with BRCA1 mutations exhibited higher mitotic counts (P = .001), a greater proportion of the tumor with a continuous pushing margin (P<.0001), and more lymphocytic infiltration (P = .002) than sporadic (i.e., control) cancers. Cancers associated with BRCA2 mutations exhibited a higher score for tubule formation (fewer tubules) (P = .0002), a higher proportion of the tumor perimeter with a continuous pushing margin (P<.0001), and a lower mitotic count (P = .003) than control cancers. CONCLUSIONS: Our study has identified key features of the histologic phenotypes of breast cancers in carriers of mutant BRCA1 and BRCA2 genes. This information may improve the classification of breast cancers in individuals with a family history of the disease and may ultimately aid in the clinical management of patients.
Assuntos
Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Genes BRCA1 , Mutação , Proteínas de Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Fatores Etários , Idoso , Proteína BRCA2 , Feminino , Humanos , Pessoa de Meia-Idade , Análise MultivariadaRESUMO
Previous studies have demonstrated that genes of the ras family (H, K, and N) can be activated by point mutations at codons 12, 13, and 61. In the present study we have used oligonucleotide probes corresponding to these regions to assess the role of ras gene mutations in the genesis of human rhabdomyosarcoma. To increase the sensitivity of this method the appropriate regions of the three ras genes were first amplified using the polymerase chain reaction. The results show that 35% (5/14) embryonal rhabdomyosarcomas investigated contain mutations in the N-ras or K-ras genes. Thus ras gene mutation is implicated in the development of mesenchymal and embryonal tumors in addition to its previously documented role in epithelial and hematological neoplasia.
Assuntos
Amplificação de Genes , Genes ras , Mutação , Reação em Cadeia da Polimerase , Rabdomiossarcoma/genética , Adolescente , Adulto , Criança , Pré-Escolar , DNA de Neoplasias/genética , DNA de Neoplasias/isolamento & purificação , DNA Polimerase Dirigida por DNA , Feminino , Humanos , Masculino , Hibridização de Ácido Nucleico , Sondas de Oligonucleotídeos , Rabdomiossarcoma/classificação , Rabdomiossarcoma/patologiaRESUMO
Lobular carcinoma in situ (LCIS) and atypical lobular hyperplasia (ALH) of the breast are cytologically similar breast lesions that reportedly carry different relative risks of subsequent development of invasive carcinoma. They are frequently multifocal and bilateral. We have identified the chromosomal copy number changes in 31 LCIS and 14 ALH lesions from 28 cases and also the 7 invasive carcinomas that subsequently developed in 6 of these cases. This was achieved by comparative genomic hybridization analysis of microdissected formalin-fixed, paraffin-embedded material. There was no significant difference between the aberrations found in the unilateral versus the bilateral cases of LCIS. Loss of material from 16p, 16q, 17p, and 22q and also gain of material from 6q were found at a similar high frequency in LCIS and ALH. Loss of these genomic regions may indicate the locations of genes that predispose to the development of the lesions, and the results are consistent with LCIS and ALH representing the same genetic stage of development. Comparison of the comparative genomic hybridization results from LCIS/ALH with those from ductal carcinoma in situ and invasive cancer showed some similarities at the chromosomal level, but it also showed significant differences, including gain of 1q and 8q and evidence for genomic amplification, which were not found in LCIS/ALH. A genetic model is postulated for the possible relationships between noninvasive lobular lesions and invasive breast carcinoma, delineating potential roles for specific chromosome copy number changes.
Assuntos
Neoplasias da Mama/genética , Carcinoma in Situ/genética , Carcinoma Lobular/genética , Aberrações Cromossômicas , Hibridização de Ácido Nucleico , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Dosagem de Genes , Humanos , Pessoa de Meia-Idade , Modelos GenéticosRESUMO
The rat mammary (Rama) epithelial stem cell line Rama 25, isolated from a dimethylbenz[a]anthracene-induced tumor, differentiates in culture into elongated cells. The uncloned elongated cells or "floaters" and one cloned elongated cell line, Rama 29, have been identified previously as containing some cells with myoepithelial characteristics. Both Rama 29 and the floaters contained a spectrum of different morphological forms, the multipolar and bipolar representatives of which were isolated by cloning cell lines. After six passages in culture, the ratio of bipolar to multipolar forms, proliferation rates, and final saturation densities usually increased, and at still higher passages, morphologically transformed foci of criss-cross cells were observed in Rama 29 cultures. From these, two morphologically transformed cell lines were isolated, Rama 29:T and Rama 521. Rama 25 and a similar subclone Rama 259, Rama 29:T, and Rama 521 readily formed tumors when injected into nude mice, whereas both the cloned (Rama 29, Rama 502, and Rama 503) and uncloned elongated cell lines (floaters) obtained directly from Rama 25 failed to do so within 12 weeks. Rama 25 and Rama 259 formed tumors which contained glandular-like areas, sheets of cuboidal cells, and spindle-cell areas, whereas Rama 29:T and Rama 521 formed tumors which contained only spindle cells. Immunocytochemistry showed that glandular areas stained with antibodies to rat milk fat globule membranes; that spindle-cell areas stained with antibodies to laminin, type IV collagen, and myosin; and that Rama 25- and Rama 259-induced tumors contained spindle-cell areas which also stained with antibodies to keratins. Ultrastructural analysis confirmed the presence of glandular-like structures and showed that spindle-cell regions contained mesenchymal-like cells with varying myoepithelial characteristics. Thus, Rama 25 and Rama 259 cells yielded some glandular-like regions and some myoepithelial cells in their tumors, while Rama 29:T and Rama 521 cells yielded some myoepithelial-like cells in their tumors without any glandular elements.
Assuntos
Neoplasias Mamárias Experimentais/fisiopatologia , Animais , Diferenciação Celular , Linhagem Celular , Cinética , Neoplasias Mamárias Experimentais/patologia , Neoplasias Mamárias Experimentais/ultraestrutura , Camundongos , Camundongos Nus , Microscopia Eletrônica , Microscopia de FluorescênciaRESUMO
An immunocytochemical method for fixed and paraffin-embedded human breast biopsies is reported for the detection of myoepithelial and epithelial cells using antibodies to myosin and keratin, respectively, and of basement membranes using antibodies to laminin and type IV collagen. Using these markers, myoepithelial cells can be clearly distinguished in the normal breast and in the benign breast diseases sclerosing adenosis, epitheliosis, and fibroadenoma. In sclerosing adenosis, myoepithelial cells form a major cellular component. A stromally derived spindle cell is identified which stains with myosin but not with keratin antibodies (myofibroblast). These cells are seen in one-fifth of the fibroadenomas. Although cells staining with myosin antibodies are seen in the infiltrating component of all 18 carcinomas examined, elongated cells staining with both myosin and keratin antibodies (myoepithelial-like) are seen in only one infiltrating carcinoma where they are interposed at the stromal-epithelial junction of the infiltrating tumor cells. In contrast to the situation in benign breast diseases, mature myoepithelial cells form a very minor component of the majority of infiltrating ductal carcinomas. Basement membrane proteins, laminin, and type IV collagen are present in normal breast, benign breast disease, and grade I infiltrating ductal carcinomas but are absent in carcinomas of grades II and III.
Assuntos
Membrana Basal/patologia , Neoplasias da Mama/patologia , Mama/patologia , Proteínas de Neoplasias/análise , Proteínas/análise , Doenças Mamárias/patologia , Carcinoma Intraductal não Infiltrante/patologia , Células Epiteliais , Feminino , HumanosRESUMO
The immunohistochemical analysis of human beta- and kappa-caseins in the human breast, benign breast disease, and breast carcinomas is reported. The monoclonal antibodies LICR-LON-32.2 and LICR-LON-14.1 which react with human beta- and kappa-casein, respectively (Earl, H. M., and McIlhinney, R. A. J. Mol. Immunol., 22: 981-991, 1985) were used for these studies. Human beta- and kappa-caseins were detected in lactating human breast tissue, lactational foci in the resting breast, and heterogeneously in the 16th-week pregnant breast, but not in normal breast tissue. In benign breast disease occasional epithelial cells were demonstrated to synthesize beta- and kappa-caseins, but this finding did not appear to correlate with the hormonal status or previous obstetric histories of the patients. However, similar studies in 45 breast carcinomas with a wide range of estrogen receptor content, demonstrated no detectable beta- or kappa-casein. These results demonstrate that the caseins, which are biochemical markers of mammary gland differentiated function, and have been previously put forward as markers of breast cancer, were not synthesized in the 45 human breast carcinomas studied here, even in tumors with high levels of estrogen receptor protein.
Assuntos
Neoplasias da Mama/patologia , Mama/citologia , Caseínas/análise , Gravidez/fisiologia , Anticorpos Monoclonais , Mama/patologia , Ensaio de Imunoadsorção Enzimática , Feminino , Doença da Mama Fibrocística/patologia , Humanos , Imuno-Histoquímica , Lactação/fisiologia , Valores de ReferênciaRESUMO
WNT-2 is a secreted polypeptide with mitogenic effects in murine mammary epithelial cells, but its role in human cancer is unknown. Using RNase protection analysis of primary cell preparations and in situ hybridization analysis, we report that WNT-2 is expressed at low levels in normal human breast fibroblasts but not in epithelial cells. WNT-2 was found to be expressed at high levels in both the epithelium and stroma of 5 of 11 infiltrating carcinomas and 2 of 6 fibroadenomas. The high level of WNT-2 expression in tumor epithelium suggests that tumorigenesis may involve the ectopic expression of WNT-2 and the creation of an autocrine Wnt signaling loop.