High frequency of germ-line BRCA2 mutations among Hungarian male breast cancer patients without family history.
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To determine the contribution of BRCA1 and BRCA2 mutations to the pathogenesis of male breast cancer in Hungary, the country with the highest male breast cancer mortality rates in continental Europe, a series of 18 male breast cancer patients and three patients with gynecomastia was analyzed for germ-line mutations in both BRCA1 and BRCA2. Although no germ-line BRCA1 mutation was observed, 6 of the 18 male breast cancer cases (33%) carried truncating mutations in the BRCA2 gene. Unexpectedly, none of them reported a family history for breast/ovarian cancer. Four of six truncating mutations were novel, and two mutations were recurrent. Four patients (22%) had a family history of breast/ovarian cancer in at least one first- or second-degree relative; however, no BRCA2 mutation was identified among them. No mutation was identified in either of the genes in the gynecomastias. These results provide evidence for a strong genetic component of male breast cancer in Hungary. (+info)
VEGFR-3 and its ligand VEGF-C are associated with angiogenesis in breast cancer.
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Recently, monoclonal antibodies against the human vascular endothelial growth factor receptor VEGFR-3 were shown to provide a specific antigenic marker for lymphatic endothelium in various normal tissues. In this study we have investigated the expression of VEGFR-3 and its ligand VEGF-C in normal breast tissue and in breast tumors by immunohistochemistry. VEGFR-3 was weakly expressed in capillaries of normal breast tissue and in fibroadenomas. In intraductal breast carcinomas, VEGFR-3 was prominent in the "necklace" vessels adjacent to the basal lamina of the tumor-filled ducts. VEGF receptor 1 and 2 as well as blood vessel endothelial and basal lamina markers were colocalized with VEGFR-3 in many of these vessels. Antibodies against smooth muscle alpha-actin gave a weak staining of the necklace vessels, suggesting that they were incompletely covered by pericytes/smooth muscle cells. A highly elevated number of VEGFR-3 positive vessels was found in invasive breast cancer in comparison with histologically normal breast tissue (P < 0.0001, the Mann-Whitney test). VEGF-C was located in the cytoplasm of intraductal and invasive cancer cells. The results demonstrate that the expression of VEGFR-3 becomes up-regulated in the endothelium of angiogenic blood vessels in breast cancer. The results also suggest that VEGF-C secreted by the intraductal carcinoma cells acts predominantly as an angiogenic growth factor for blood vessels, although this paracrine signaling network between the cancer cells and the endothelium may also be involved in modifying the permeabilities of both blood and lymphatic vessels and metastasis formation. (+info)
Vascular stroma formation in carcinoma in situ, invasive carcinoma, and metastatic carcinoma of the breast.
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The generation of vascular stroma is essential for solid tumor growth and involves stimulatory and inhibiting factors as well as stromal components that regulate functions such as cellular adhesion, migration, and gene expression. In an effort to obtain a more integrated understanding of vascular stroma formation in breast carcinoma, we examined expression of the angiogenic factor vascular permeability factor (VPF)/vascular endothelial growth factor (VEGF); the VPF/VEGF receptors flt-1 and KDR; thrombospondin-1, which has been reported to inhibit angiogenesis; and the stromal components collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin by mRNA in situ hybridization on frozen sections of 113 blocks of breast tissue from 68 patients including 28 sections of breast tissue without malignancy, 18 with in situ carcinomas, 56 with invasive carcinomas, and 8 with metastatic carcinomas. A characteristic expression profile emerged that was remarkably similar in invasive carcinoma, carcinoma in situ, and metastatic carcinoma, with the following characteristics: strong tumor cell expression of VPF/VEGF; strong endothelial cell expression of VPF/VEGF receptors; strong expression of thrombospondin-1 by stromal cells and occasionally by tumor cells; and strong stromal cell expression of collagen type I, total fibronectin, ED-A+ fibronectin, versican, and decorin. The formation of vascular stroma preceded invasion, raising the possibility that tumor cells invade not into normal breast stroma but rather into a richly vascular stroma that they have induced. Similarly, tumor cells at sites of metastasis appear to induce the vascular stroma in which they grow. We conclude that a distinct pattern of mRNA expression characterizes the generation of vascular stroma in breast cancer and that the formation of vascular stroma may play a role not only in growth of the primary tumor but also in invasion and metastasis. (+info)
An audit of breast cancer pathology reporting in Australia in 1995.
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To measure the quality of pathology reporting of breast cancer and establish a baseline against which future changes can be measured, we audited item completeness in breast cancer reports in Australia in 1995 before the release of specific recommendations from the Australian Cancer Network. Tumour type and size were given in reports of invasive breast cancer for 93% of women, 70% had, in addition, grade and clearance of the margins while only 28% had all recommended information. The most complete items in reports were histological type of breast cancer (99.6% of cases), tumour size (94%, 95% confidence interval (CI) 92-95) and margins of excision (87%, 95% CI 85-89). Histological grade (84%, 95% CI 82-86 of cases) and presence or absence of ductal carcinoma in situ (DCIS) (79%, 95% CI 77-81) were less complete and vessel invasion (61%, 95% CI 58-63) and changes in non-neoplastic breast tissue adjacent to the breast cancer (68%, 95% CI 66-71) the least complete. Less than half the reports of DCIS reported on tumour size (49%, 95% CI 42-57), presence or absence of necrosis (41%, 95% CI 34-49) or nuclear grade (39%, 95% CI 31-46). Around 1500 reports were identified as issued by 147 laboratories and 392 pathologists; 69% of pathologists issued fewer than two reports a month in the audit. We concluded that infrequency of reporting may have contributed to incompleteness of reporting. In addition, we found significant variation across Australian states with some indication that reporting was consistently poor in one state. The audit highlighted areas for improvement for breast cancer reporting in Australia. Research evidence suggests that multifaceted strategies are needed to assist practitioners with implementing more uniform reporting standards. (+info)
Urokinase plasminogen activator receptor (CD87) expression of tumor-associated macrophages in ductal carcinoma in situ, breast cancer, and resident macrophages of normal breast tissue.
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Macrophages concentrate urokinase-type plasminogen activator (uPA) at the cell surface by expressing urokinase receptors (uPAR) in order to focus the pericellular space plasminogen-dependent proteolysis important in matrix remodeling and cell movement. This study examines the uPAR levels of tumor-associated macrophages (TAM) of invasive breast carcinomas, of TAMs from ductal carcinoma in situ (DCIS) and of macrophages derived from normal (non-tumor) breast tissue. TAMs from invasive breast carcinomas (n = 30), from DCIS (n = 12), and macrophages from normal breast tissue (n = 30) were cultured and immunocytochemically phenotyped by using a panel of antibodies. Urokinase receptor levels were determined by Western blot analysis and in cell-free supernatants by enzyme-linked immunosorbent assay. Urokinase receptor cell surface fluorescence intensity was determined by FACS and by confocal laser scan microscopy. Urokinase-receptor mRNA was detected by in situ hybridization. TAMs of invasive breast carcinomas and of DCIS possess significantly elevated uPAR levels compared with macrophages derived from normal breast tissue. CONCLUSIONS: activated macrophages with elevated uPAR levels belong to inflammatory areas in close vicinity of infiltrating and non-infiltrating (DCIS) tumor cells. Blood monocytes that possess elevated uPAR-levels may be selectively recruited from the bloodstream to inflammatory sites close to carcinoma cells, and/or breast cancer and precursor lesions may induce elevated uPAR-levels in TAMs by paracrine interactions. (+info)
Primary tumour characteristics and axillary lymph node status in breast cancer.
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This paper examines the correlation between axillary lymph node status and primary tumour characteristics in breast cancer and whether this can be used to select patients for axillary lymphadenectomy. The results are based on a retrospective analysis of 909 patients who underwent axillary dissection in our unit. Axillary lymph nodes containing metastases were found in 406 patients (44.7%), all with invasive carcinomas, but in none of the 37 carcinomas-in-situ. Nodal status was negative in all T1a tumours, but lymph node metastases were present in 16.3% and 35.7% of T1b and T1c tumours respectively. When histological grade was taken into account, positivity for grade I T1b and T1c tumours fell to 13.6% and 26.7% respectively. Lymph node metastases were found in 85% of patients with lymphovascular invasion in their tumours as compared to only 15.4% of those without and in 45.5% of oestrogen and progesterone receptor-positive tumours. When one or both hormone receptors were absent this figure was much higher. It appears that for T1a breast cancers axillary dissection is not necessary, whereas for T1b, T1c and grade I T2 tumours other histopathological parameters should be taken into consideration in deciding who should undergo axillary lymphadenectomy. (+info)
Elevated expression of the CC chemokine regulated on activation, normal T cell expressed and secreted (RANTES) in advanced breast carcinoma.
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Breast carcinoma is the most common malignant disease among women and the second most lethal one. In search for a better understanding of the role of cellular mediators in the progression of this disease, we investigated the potential involvement of the CC chemokine Regulated on Activation, Normal T Cell Expressed and Secreted (RANTES) in breast carcinoma progression. To this end, RANTES expression was determined in breast tumor cell lines and in sections of breast carcinomas, followed by analysis of the incidence and intensity of its expression in different stages of the disease. Our study reveals that high and physiologically relevant levels of RANTES are constitutively produced by T47D and MCF-7 breast tumor cell lines. Analysis of RANTES expression in sections of breast carcinomas demonstrates a high incidence of RANTES expression in epithelial tumor cells; the chemokine was expressed in 74% of the sections. RANTES expression was rarely detected in normal duct epithelial cells or in epithelial cells that constitute benign breast lumps, which were located in proximity to tumor cells. High incidence and intensity of RANTES expression were detected in sections of most of the patients with stage II and stage III of the disease (expression was detected in 83 and 83.3%, respectively), whereas RANTES was expressed at a lower incidence and intensity in sections of patients with stage I of breast carcinoma (55% of the cases). Most importantly, the expression of RANTES was minimally detected in sections of patients diagnosed with benign breast disorders and of women that underwent reduction mammoplasty (15.4% of the cases). These results indicate that the expression of RANTES is directly correlated with a more advanced stage of disease, suggesting that RANTES may be involved in breast cancer progression. Moreover, it is possible that in patients diagnosed with benign breast disorders, RANTES expression may be indicative of an ongoing, but as yet undetectable, malignant process. (+info)
Prognosis in women with a carcinoma in situ of the breast: a population-based study in Sweden.
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We studied the risk of invasive breast cancer and breast cancer death after a breast carcinoma in situ during a period when mammography screening became a nationwide practice and when breast conservation was introduced. In a study base including all 4661 women registered to the Swedish Cancer Registry for a first carcinoma in situ between 1960 and 1992, we selected a cohort of 3398 women diagnosed between 1980 and 1992. The recruitment period was chosen according to the reporting routines for the registry. The corrected survival was 97.4% after 10 years. The risk of invasive cancer was similar in the ipsilateral and contralateral breast. Women diagnosed between 1989 and 1992 ran a relative risk of 0.1 (95% confidence interval, 0.0-0.9) of dying of breast cancer, as compared with women diagnosed from 1980-1982. Residence in counties where mammography screening was available was associated with a relative risk of 0.2 (95% confidence interval, 0.0-2.1) for breast cancer death in the age groups screened. Screening mammography may have contributed to the improvement of prognosis over this time period. This study cannot distinguish between lead time effects and a "true" improvement in prognosis. The increased use of breast conservation was not associated with a worse prognosis in the group as a whole. The study indicates that at least 50% of invasive cancers occurring after treatment for in situ lesions may be new cancers. (+info)