Mucin expression in mucinous carcinoma and other invasive carcinomas of the breast.

To investigate mucin expression in breast cancer, immunohistochemical staining was performed on 30 mucinous carcinomas and 95 non-mucinous invasive carcinomas. MUC2 expression was detected in all mucinous carcinomas, but only in 11.1% of invasive ductal carcinomas, and in none of the invasive lobular carcinomas and medullary carcinomas. MUC1 is often expressed in invasive breast carcinoma, but not in medullary carcinoma. Strong cytoplasmic staining was seen in invasive ductal carcinoma, in contrast to surface membrane staining in mucinous carcinoma and intracytoplasmic vacuole staining in invasive lobular carcinoma. CA19-9 and CA50 expression in more than 25% of tumor cells was seen in 17.2 and 16.0% of invasive ductal carcinomas, respectively, but not in mucinous carcinomas. CA125 and human gastric mucin were rarely expressed in breast cancer, irrespective of histologic type.     

Increased N-myc downstream-regulated gene 1 expression is associated with breast atypia-to-carcinoma progression

N-myc downstream-regulated gene-1 (NDRG1) has been identified as a protein involved in the differentiation of epithelial cells. As a newly metastasis suppressor gene, whether it contributes to carcinogenesis of breast cancer is still unknown. This study aimed to clarify the possible role of NDRG1 for breast cancer carcinogenesis, and further to investigate its clinicopathological significance in invasive breast cancer. We examined the expression of NDRG1 in normal epithelium of breast (n = 35), usual ductal hyperplasia (n = 22), atypical ductal hyperplasia (n = 33), atypical lobular hyperplasia (n = 8), ductal carcinoma in situ (n = 16), lobular carcinoma in situ (n = 6), invasive ductal carcinoma (n = 50), and invasive lobular carcinoma (n = 45) by immunohistochemistry and analyzed the correlation between NDRG expression and clinicopathological features of invasive breast cancer. Western blot analysis was carried out to investigate the expression of NDRG1 in 20 invasive ductal breast cancer and the paired non-tumor portion of the same case. NDRG1 expression in invasive breast cancer (70/95, 73.7%) was higher than that in noninvasive breast lesions (29/85, 34.1%; p < 0.05) which was higher than that in normal breast epithelium (5/35, 14.3%; p < 0.05). Statistical analysis revealed a significant correlation between NDRG1 expression with tumor stage in invasive breast cancer, and its expression in invasive ductal carcinoma is significantly higher than invasive lobular carcinoma (p < 0.05). It was not associated with age, menopausal status, tumor size, and lymph node metastasis. NDRG1 protein levels were significantly higher in invasive ductal breast cancer compared to the paired non-tumor portion of the same case by Western blot analysis (p < 0.05). Increased NDRG-1 expression is associated with breast atypia-to-carcinoma progression. NDRG1 expression might participate in the carcinogenesis and progression of invasive breast cancer. These findings provide further evidence that NDRG1 may serve as an important biomarker for invasive breast cancer.     

Immunohistochemical demonstration of metallothionein in normal human breast tissue and benign and malignant breast lesions

Metallothioneins (MTs) are a set of low molecular weight proteins with a high binding affinity to metal ions. MT over-expression has been recently demonstrated in invasive ductal carcinoma of the breast with poor clinical prognosis. In the present study, MTs have been immunohistochemically investigated in normal human breast tissue and a variety of benign, pre-invasive, and malignant breast lesions. In normal breast tissue, MTs were present in myoepithelial cells whereas the vast majority of luminal cells were MT negative. In lesions without increased cancer risk (adenosis and scleradenosis), MT was only immunolocalized in myoepithelial cells. In papillomas, MT was also found exclusively in myoepithelial cells. In most cases of epitheliosis, both the luminal and myoepithelial cells expressed MT. Atypicallobular hyperplasia, lobular carcinomain situ, and 13/15 invasive lobular carcinomas showed no MT over-expression. The two invasive lobular carcinomas with MT over-expression were classified as pleomorphic lobular carcinomas with apocrine differentiation. In contrast to lobular cancerization, 12/24 ductalin situ carcinomas and 9/20 invasive ductal carcinomas showed MT over-expression.In situ components found within invasive ductal carcinomas usually reflected the MT status of their invasive counterpart. It is concluded from our immunohistochemical results that breast carcinoma cases with MT overexpression arise from lesions which also show MT overexpression. Thus MT expression in carcinomas may be regarded as a genuine feature of the tumour cells and seems not to be related to endogenous or exogenous factors known to induce MT synthesis.     

乳腺癌HER2基因扩增的临床病理意义

目的 检测乳腺癌组织中HER2基因扩增状态,评价其临床病理意义。方法 应用FISH、IHC方法分析55例乳腺癌HER2基因扩增/蛋白表达状态与临床病理特征的关系,比对IHC法与FISH检测的一致性程度。结果 55例乳腺癌FISH检测有32例（58.2%）HER2基因扩增。IHC法HER2（+++）22例中21例（95.5%）HER2基因扩增;HER2（++）12例中10例（83.3%）HER2基因扩增;HER2（+/－）21例中1例（4.7%）HER2基因扩增。39例浸润性导管癌中30例（76.9%）有HER2基因扩增,12例浸润性小叶癌中仅1例（8.3%）HER2基因扩增。HER2基因扩增在浸润性导管癌的组织学分级间差异有统计学意义（P<0.001）,组织学Ⅲ级的浸润性导管癌较Ⅰ、Ⅱ级有较高的HER2基因扩增率。HER2基因扩增与ER、PR阴性状态及腋淋巴结转移有显著相关性（P<0.01）,与患者是否绝经无相关性（P>0.05）。结论 浸润性小叶癌,ER、PR阳性以及组织学Ⅰ级的浸润性导管癌常少有HER2基因扩增;对于组织学Ⅲ的浸润性导管癌,同时ER、PR阴性者尽管IHC检测结果为阴性,仍需做FISH检测以明确是否有HER2基因扩增。     

Diffuse growth pattern affects E-cadherin expression in invasive breast cancer

We investigated the correlations between growth patterns and E-cadherin expression by immunohistochemistry and the presence of mutations of exons 6-10 of the E-cadherin gene by PCR-SSCP, in 79 cases of invasive lobular and ductal breast cancer. E-cadherin expression showed a tendency to be lower in lobular than in ductal carcinomas (p=0.064). In 60% of lobular carcinomas the diffuse growth pattern and in 72% of ductal carcinomas the compact growth pattern predominated. E-cadherin expression was significantly lower in diffuse than in compact tumor area (p<0.001) and not related to carcinoma type when it was considered in tumor areas with either diffuse (p=0.278) or compact (p=0.128) growth pattern. No mutations were detected. In conclusion, loss of E-cadherin expression is related to an increase of diffuse growth pattern in both lobular and ductal types of breast cancer, and the differential proportions of growth patterns in both tumor types cause the tendency for lower E-cadherin expression in the lobular type.     

Lack of prognostic significance of "classic" lobular breast carcinoma: a matched, single institution series

Whether invasive lobular carcinoma of the breast per se constitutes a prognostically favorable type has been debated. The present series comprises 301 consecutive “classic” lobular breast carcinomas seen at one institution between 1994 and 2001, compared to an equal number of invasive ductal carcinomas at the same institution during the same period, matched for year of surgery, age, menopausal status, primary tumor size, nodal involvement, hormone receptor status and where possible histological grade. Despite matching, the lobular carcinomas were more frequently multifocal, had more involved nodes, lower grade and lower proliferative fraction. There was no significant difference in disease-free or overall survival, locoregional relapse or time to distant metastasis between the lobular and ductal groups overall or within any examined subset, though the lobular group showed a trend to earlier appearance of contralateral breast cancer. Classical lobular histology is not an independent factor in the prognosis of early breast cancer.     

Expression patterns of beta-catenin in in situ and invasive breast cancer.

BACKGROUND: beta-Catenin plays a central role in the E-cadherin/catenin cell-cell adhesion complex and is possibly involved in cellular signalling pathways. In this study, we evaluated the expression patterns of this molecule in in situ and invasive breast cancer. METHODS: The expression of beta-catenin was evaluated in 121 breast cancer specimens by immunohistochemistry. Its relationship to clinicopathological features was also investigated. RESULTS: Altered beta-catenin expression was found in 68% of tumours. Lobular carcinomas showed abnormal beta-catenin expression more frequently (77%) than ductal carcinomas (64%) with 46% of lobular cases showing complete absence of beta-catenin immunoreactivity. Cytoplasmic beta-catenin localization was seen only in ductal carcinomas. Aberrant beta-catenin expression was observed in 54% of ductal carcinomas in situ with highly concordant beta-catenin expression patterns in the nearby in situ and invasive components. CONCLUSIONS: Quantitative and qualitative changes in beta-catenin expression occur in a considerable proportion of in situ and invasive ductal carcinomas and are more prominent in invasive lobular carcinomas. Copyright Harcourt Publishers Limited.     

Regional variations in breast cancer incidence among California women, 1988–1997

Background: Internationally, California has some of the highest breast cancer rates; these rates also show substantial regional variations within the state. This study describes geographic breast cancer incidence patterns within California and evaluates the degree to which socioeconomic status (SES) and urbanization explain the regional variability.Methods: Invasive breast cancer cases in women 20 year of age were identified from the California Cancer Registry, for 1988–1997, then assigned to one of three regions (San Francisco Bay Area, Southern Coastal Area and the rest of California), based on residence at diagnosis. Neighborhood SES and urbanization were derived from U.S. Census data. Rate ratios (RR) and 95% confidence intervals (CI) were computed using Poisson regression. Analyses were conducted for all invasive breast cancer cases (n=176,302) and by selected histologic subtypes: ductal (n=121,619); lobular (n=13,410); mixed ductal and lobular (n=9744).Results: Compared to block groups with the lowest quartile of SES, rates were highest in block groups with high SES. Rates also were higher in suburban and city areas than in small town/rural areas. Compared to the rest of California, age- and race-adjusted rates for all breast cancer were approximately 20% higher in the San Francisco Bay Area and 10% higher in the Southern Coastal Area. After adjusting for SES and urbanization the rate ratios were reduced to near unity (RR=1.06, 95% CI: 1.03–1.09 for San Francisco Bay Area; RR=1.02, 95% CI: 0.99–1.04 for Southern Coastal Area). Rates ratios for ductal carcinomas mirrored those for all cases. For lobular cases, rate ratios remained elevated after adjustment for age, race/ethnicity, neighborhood SES and urbanization (RR=1.18, 95% CI: 1.11–1.27 for San Francisco Bay Area; RR=1.10, 95% CI: 1.04–1.17 for Southern Coastal Area). For the subset of cases with mixed ductal and lobular histologies, the rate ratio for the San Francisco Bay Area was no longer elevated after adjusting for age, race/ethnicity, SES and urbanization (RR=0.92, 95% CI: 0.84–1.01); the adjusted rate ratio for the Southern Coastal Area, however, remained elevated (RR=1.22, 95% CI: 1.12–1.32).Conclusions: Regional differences in neighborhood SES and urbanization appear to largely explain regional rate differences in California for all breast cancers and ductal carcinomas but do not fully explain geographic patterns of breast cancer with a lobular component.     

Elafin is downregulated during breast and ovarian tumorigenesis but its residual expression predicts recurrence

IntroductionElafin is an endogenous serine protease inhibitor. The majority of breast cancer cell lines lack elafin expression compared to human mammary epithelial cells. In this study, we hypothesized that elafin is downregulated during breast and ovarian tumorigenesis.MethodsWe examined elafin expression by immunohistochemistry (IHC) in specimens of normal breast tissue (n = 24), ductal carcinoma in situ (DCIS) (n = 54), and invasive breast cancer (n = 793). IHC analysis of elafin expression was also performed in normal fallopian tube tissue (n = 20), ovarian cystadenomas (n = 9), borderline ovarian tumors (n = 21), and invasive ovarian carcinomas (n = 216). To understand the significance of elafin in luminal breast cancer cell lines, wild-type or M25G elafin (lacking the protease inhibitory function) were exogenously expressed in MCF-7 and T47D cells.ResultsElafin expression was downregulated in 24% of DCIS and 83% of invasive breast tumors when compared to elafin expression in the normal mammary epithelium. However, the presence of elafin-positive cells in invasive breast tumors, even at low frequency, correlated with poor recurrence-free survival (RFS), reduced overall survival (OS), and clinicopathological markers of aggressive tumor behavior. Elafin-positive cells were an especially strong and independent prognostic marker of reduced RFS in IHC-defined luminal A-like tumors. Elafin was also downregulated in 33% of ovarian cystadenomas, 43% of borderline ovarian tumors, and 86% of invasive ovarian carcinomas when compared to elafin expression in the normal fallopian tube. In ovarian tumors, elafin-positive cells were correlated with reduced RFS, OS and disease-specific survival (DSS) only in stage I/II patients and not in stage III/IV patients. Notably, exogenous expression of elafin or elafin M25G in the luminal breast cancer cell lines MCF-7 and T47D significantly decreased cell proliferation in a protease inhibitory domain-independent manner.ConclusionsElafin predicts poor outcome in breast and ovarian cancer patients and delineates a subset of endocrine receptor-positive breast cancer patients susceptible to recurrence who could benefit from more aggressive intervention. Our in vitro results suggest that elafin arrests luminal breast cancer cells, perhaps suggesting a role in tumor dormancy.

Electronic supplementary material

The online version of this article (doi:10.1186/s13058-014-0497-4) contains supplementary material, which is available to authorized users.     

Invasive breast cancer following ductal and lobular carcinoma in situ of the breast

We considered the risk of subsequent invasive breast cancer in a population-based series of 579 carcinomas in situ (CIS) of the breast (482 ductal, 88 lobular) registered between 1977 and 2002 in the Swiss Canton of Vaud. A total of 55 cases of invasive breast cancer were observed vs. 12.3 expected, corresponding to a standardized incidence ratio (SIR) of 4.5 (95% confidence interval [CI], 3.4-5.8). The SIR was 4.6 after ductal and 4.2 after lobular CIS, was similar with passing time since CIS diagnosis, but was higher (SIR = 5.5) for women aged <55 years. At 20 years following CIS, the cumulative risk of invasive breast cancer was 26%, similar for lobular and for ductal CIS. The incidence of invasive breast cancer following CIS showed no consistent pattern of trends with age, all rates in subsequent age groups ranging between 10 and 18 in 1,000. This is compatible with the occurrence of a single mutational event in a population of susceptible women.     

Serum metabolomic profiles evaluated after surgery may identify patients with oestrogen receptor negative early breast cancer at increased risk of disease recurrence. Results from a retrospective study

Purpose

Metabolomics is a global study of metabolites in biological samples. In this study we explored whether serum metabolomic spectra could distinguish between early and metastatic breast cancer patients and predict disease relapse.

Methods

Serum samples were analysed from women with metastatic (n = 95) and predominantly oestrogen receptor (ER) negative early stage (n = 80) breast cancer using high resolution nuclear magnetic resonance spectroscopy. Multivariate statistics and a Random Forest classifier were used to create a prognostic model for disease relapse in early patients.

Results

In the early breast cancer training set (n = 40), metabolomics correctly distinguished between early and metastatic disease in 83.7% of cases. A prognostic risk model predicted relapse with 90% sensitivity (95% CI 74.9–94.8%), 67% specificity (95% CI 63.0–73.4%) and 73% predictive accuracy (95% CI 70.6–74.8%). These results were reproduced in an independent early breast cancer set (n = 40), with 82% sensitivity, 72% specificity and 75% predictive accuracy. Disease relapse was associated with significantly lower levels of histidine (p = 0.0003) and higher levels of glucose (p = 0.01), and lipids (p = 0.0003), compared with patients with no relapse.

Conclusions

The performance of a serum metabolomic prognostic model for disease relapse in individuals with ER‐negative early stage breast cancer is promising. A confirmation study is ongoing to better define the potential of metabolomics as a host and tumour‐derived prognostic tool.     

Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas.

Combined estrogen and progestin hormone therapy (CHT) increases breast cancer risk, but this risk varies by breast cancer type. Several studies indicate that CHT is more strongly related to lobular carcinoma risk than to ductal carcinoma risk, but these studies have been limited in their assessments of recency and duration of use, and none included a centralized pathology review. We conducted a population-based case-control study consisting of 324 lobular, 196 ductal-lobular, and 524 ductal cases diagnosed from 2000 to 2004 and 469 controls ages 55 to 74 years old. Tissue specimens were centrally reviewed for 83% of cases. Associations between hormone use and breast cancer risk were evaluated using polytomous logistic regression. Current CHT users had 2.7-fold [95% confidence interval (95% CI), 1.7-4.2] and 3.3-fold (95% CI, 2.0-5.7) elevated risks of lobular and ductal-lobular carcinomas, respectively, regardless of tumor stage, size, or nodal status. Elevations in risk were observed only among users of CHT for > or =3 years. Among ductal-lobular cases, CHT increased risk of tumors that were > or =50% lobular (odds ratio, 4.8; 95% CI, 2.1-11.1) but not tumors that were <50% lobular (odds ratio, 1.9; 95% CI, 0.9-4.1). Current CHT users for > or =3 years have a substantially increased risk of lobular carcinomas. Although lobular carcinomas are less common than ductal carcinomas ( approximately 16% versus 70% of all invasive breast cancers in the United States), this duration is shorter than the 5 years of use widely cited to be needed to confer an increased risk of breast cancer overall. Further studies focusing on the etiology of lobular carcinomas are needed.     

Sortilin is associated with breast cancer aggressiveness and contributes to tumor cell adhesion and invasion

The neuronal membrane protein sortilin has been reported in a few cancer cell lines, but its expression and impact in human tumors is unclear. In this study, sortilin was analyzed by immunohistochemistry in a series of 318 clinically annotated breast cancers and 53 normal breast tissues. Sortilin was detected in epithelial cells, with increased levels in cancers, as compared to normal tissues (p = 0.0088). It was found in 79% of invasive ductal carcinomas and 54% of invasive lobular carcinomas (p < 0.0001). There was an association between sortilin expression and lymph node involvement (p = 0.0093), suggesting a relationship with metastatic potential. In cell culture, sortilin levels were higher in cancer cell lines compared to non-tumorigenic breast epithelial cells and siRNA knockdown of sortilin inhibited cancer cell adhesion, while proliferation and apoptosis were not affected. Breast cancer cell migration and invasion were also inhibited by sortilin knockdown, with a decrease in focal adhesion kinase and SRC phosphorylation. In conclusion, sortilin participates in breast tumor aggressiveness and may constitute a new therapeutic target against tumor cell invasion.     

Genomic and protein expression analysis reveals flap endonuclease 1 (FEN1) as a key biomarker in breast and ovarian cancer

FEN1 has key roles in Okazaki fragment maturation during replication, long patch base excision repair, rescue of stalled replication forks, maintenance of telomere stability and apoptosis. FEN1 may be dysregulated in breast and ovarian cancers and have clinicopathological significance in patients. We comprehensively investigated FEN1 mRNA expression in multiple cohorts of breast cancer [training set (128), test set (249), external validation (1952)]. FEN1 protein expression was evaluated in 568 oestrogen receptor (ER) negative breast cancers, 894 ER positive breast cancers and 156 ovarian epithelial cancers. FEN1 mRNA overexpression was highly significantly associated with high grade (p = 4.89 × 10−57), high mitotic index (p = 5.25 × 10−28), pleomorphism (p = 6.31 × 10−19), ER negative (p = 9.02 × 10−35), PR negative (p = 9.24 × 10−24), triple negative phenotype (p = 6.67 × 10−21), PAM50.Her2 (p = 5.19 × 10−13), PAM50. Basal (p = 2.7 × 10−41), PAM50.LumB (p = 1.56 × 10−26), integrative molecular cluster 1 (intClust.1) (p = 7.47 × 10−12), intClust.5 (p = 4.05 × 10−12) and intClust. 10 (p = 7.59 × 10−38) breast cancers. FEN1 mRNA overexpression is associated with poor breast cancer specific survival in univariate (p = 4.4 × 10−16) and multivariate analysis (p = 9.19 × 10−7). At the protein level, in ER positive tumours, FEN1 overexpression remains significantly linked to high grade, high mitotic index and pleomorphism (ps < 0.01). In ER negative tumours, high FEN1 is significantly associated with pleomorphism, tumour type, lymphovascular invasion, triple negative phenotype, EGFR and HER2 expression (ps < 0.05). In ER positive as well as in ER negative tumours, FEN1 protein overexpression is associated with poor survival in univariate and multivariate analysis (ps < 0.01). In ovarian epithelial cancers, similarly, FEN1 overexpression is associated with high grade, high stage and poor survival (ps < 0.05). We conclude that FEN1 is a promising biomarker in breast and ovarian epithelial cancer.     

Lack of cyclin E immunoreactivity in non-malignant breast and association with proliferation in breast cancer.

Cyclin E is a G1 cyclin that is essential for the transition from G1 to S phase in the cell cycle. Alterations to cyclin E expression or regulation could be important in tumorigenesis. Previous immunohistochemical and immunoblotting studies have investigated the expression of cyclin E in breast carcinomas. In this study, cyclin E has been investigated in a range of non-malignant and malignant breast using immunohistochemistry. Normal and benign tissue from pre- and post-menopausal women (39 cases), non-involved tissue from cancer-containing breasts (47 cases), ductal carcinoma in situ (22 cases) and invasive breast carcinomas (109 cases) have been examined. There was no reactivity in any of the non-malignant breast. Only one ductal carcinoma in situ contained more than 5% reactive cells. A total of 28% of invasive carcinomas had > 5% of reactive cells (range 0-88% positive cells, mean 12.59%, median 1.0%). A significant association was found with poorer differentiation (P < 0.001), high MIB1 index (P < 0.001), lack of oestrogen receptor (0.05 > P > 0.025) and the presence of p53 protein (0.05 > P > 0.025). Virtually all cases with cyclin E and p53 were poorly differentiated. The presence of cyclin E is therefore only found in breast malignancies and is associated with more aggressive features, including high proliferation.     

Reproductive factors and histologic subtype in relation to mortality after a breast cancer diagnosis

Evidence suggests that certain reproductive factors are more strongly associated with the incidence of lobular than of ductal breast cancer. The mechanisms influencing breast cancer incidence histology may also affect survival. Women with invasive breast cancer (N = 22,302) diagnosed during 1986–2005 were enrolled in a series of population-based studies in three US states. Participants completed telephone interviews regarding reproductive exposures and other breast cancer risk factors. Histologic subtype was obtained from state cancer registries. Vital status and cause of death were determined through December 2006 using the National Death Index. Women were followed for 9.8 years on average with 3,050 breast cancer deaths documented. Adjusted hazard rate ratios (HR) and 95% confidence intervals (95% CI) were calculated using Cox proportional hazards regression models for breast cancer-specific and all-cause mortality. Parity was inversely associated with breast cancer-specific mortality (P _Trend = 0.002). Associations were similar though attenuated for all-cause mortality. In women diagnosed with ductal breast cancer, a 15% reduction in breast cancer-specific mortality was observed in women with five or more children when compared to those with no children (HR = 0.85, 95% CI: 0.73–1.00). A similar inverse though non-significant association was observed in women with lobular subtype (HR = 0.70, 95% CI: 0.43–1.14). The trend did not extend to mixed ductal–lobular breast cancer. Age at first birth had no consistent relationship with breast cancer-specific or all-cause mortality. We found increasing parity reduced mortality in ductal and lobular breast cancer. The number of full-term births, rather than age at first birth, has an effect on both breast cancer-specific and overall mortality.     

Founder BRCA1 and BRCA2 mutations in early-onset French Canadian breast cancer cases unselected for family history

Recently, founder BRCA1 and BRCA2 mutations were identified in Canadian breast cancer and breast-ovarian cancer families of French ancestry. The presence of a breast cancer case diagnosed at younger than 36 years of age was strongly predictive of the presence of any founder mutation screened. Here we report the occurrence of founder BRCA1 and BRCA2 mutations in a series of 61 French Canadian women with invasive breast cancer diagnosed at age 40 or younger, unselected for family history of breast and ovarian cancer. Germline mutations in BRCA1 (n = 4) and BRCA2 (n = 4) were identified in 8 of 61 (13%) cases. All BRCA1 mutations were found in invasive ductal carcinomas, the most common histologic type of tumor in this series. In contrast, the BRCA2 mutations were found in tumors of various histologic types: two ductal carcinomas, a tumor containing both ductal and lobular histologic types and an invasive lobular carcinoma. Of the 37 women with at least one first-, second- or third-degree relative with breast or ovarian cancer and the 24 women with no history of these cancers, 7 (19%) and 1 (4%), respectively, were mutation carriers. The seven mutation carriers with a family history of cancer had at least one first-, second- or third-degree relative with a breast cancer diagnosis at less than 51 years of age. The identification of founder BRCA1 and BRCA2 mutations in young-onset breast cancer cases unselected for family history can facilitate carrier detection when the expected yield of a comprehensive screen may be low.     

Expression of c-erbB3 protein in primary breast carcinomas.

Expression of c-erbB3 protein was investigated in 104 primary breast carcinomas comprising nine comedo ductal carcinoma in situ (DCIS), 91 invasive ductal carcinomas and four invasive lobular carcinomas using two monoclonal antibodies, RTJ1 and RTJ2. Of the 91 invasive ductal carcinomas, seven contained the comedo DCIS component adjacent to the invasive component. An immunohistochemical technique was used to evaluate the association between expression of c-erbB3 and clinical parameters and tumour markers such as epidermal growth factor receptor (EGFR), c-erbB2, cathepsin-D and p53 in archival formalin-fixed paraffin-embedded tumour tissues. Our results indicated that RTJ1 and RTJ2 gave identical staining patterns and concordant results. It was found that the overexpression of c-erbB3 protein was observed in 67% (6/9) of comedo DCIS, 52% (44/84) of invasive ductal carcinomas, 71% (5/7) of carcinomas containing both the in situ and invasive lesions and 25% (1/4) of invasive lobular carcinomas. A significant relationship (P < 0.05) was observed between strong immunoreactivity of c-erbB3 protein and histological grade, EGFR and cathepsin-D, but not with expression of c-erbB2, p53, oestrogen receptor status, lymph node metastases or age of patient. However, we noted that a high percentage of oestrogen receptor-negative tumours (59%), lymph node-positive tumours (63%) and c-erbB2 (63%) were strongly positive for c-erbB3 protein. We have also documented that a high percentage of EGFR (67%), c-erbB2 (67%), p53 (75%) and cathepsin-D-positive DCIS (60%) were strongly positive for c-erbB3. These observations suggest that overexpression of c-erbB3 protein could play an important role in tumour progression from non-invasive to invasive and, also, that it may have the potential to be used as a marker for poor prognosis of breast cancer.     

Immunohistochemical distribution of c-erbB-2 in infiltrating and in situ breast cancer

An immunohistochemical study of c-erbB-2 expression was performed on invasive and in situ breast cancer. Strong membrane staining was seen in 16% of the infiltrating ductal carcinomas and 44% of the in situ lesions. c-erbB-2 was overexpressed in ductal rather than lobular tumours. Our results indicate that a small sub-group of breast carcinomas are associated with over-expression of this oncogene which may define an important subgroup of in situ and infiltrating ductal carcinomas.