p53 protein expression in human breast carcinoma: relationship to expression of epidermal growth factor receptor, c-erbB-2 protein overexpression, and oestrogen receptor.

The expression of p53 protein, oestrogen receptor protein, epidermal growth factor receptor (EGFR) and overexpression of the c-erbB-2 oncoprotein was examined in a series of 149 primary symptomatic breast carcinomas. Expression of p53 was present in 62 of 146 cases (42.5%) of the invasive carcinoma and one of three cases (33.3%) of ductal carcinoma in situ (DCIS) examined. Statistical associations of tumour oestrogen receptor positivity and lack of p53 protein expression, chi 2 = 19.78 (d.f. = 1), P less than 0.001, positive tumour p53 status and poor tumour grade; chi 2 = 14.1 (d.f. = 2), P less than 0.001, EGFR expression chi 2 = 7.07, (d.f. = 1), P less than 0.01 and tumour c-erbB-2 protein overexpression; chi 2 = 4.61 (d.f. = 1), P = 0.032 were identified. Expression of p53 is rare in invasive lobular carcinoma of classical type (8.3% of cases examined) in contrast to other common types of mammary carcinoma. Non-significant trends of p53 protein expression and increased regional tumour recurrence; chi 2 = 3.20 (d.f. = 1), P = 0.074 and also poorer patient survival; chi 2 = 3.76 (d.f. = 1), P = 0.053 were identified. p53 protein expression is a common event in human breast cancer and is present in both DCIS and invasive mammary carcinoma. Abnormal expression of p53 protein is a feature of both in situ and invasive breast carcinoma, implying that the abnormal p53 protein expression may be implicated in the early stages of mammary carcinoma progression.     

Expression and amplification of cyclin D1 in primary breast carcinomas: relationship with histopathological types and clinico-pathological parameters

Overexpression and amplification of cyclin D1 were investigated by immunohistochemistry and differential polymerase chain reaction (dPCR) in 440 formalin-fixed primary breast carcinoma tissues. Overexpression of cyclin D1 was detected in 60% (263/440) and amplification of cyclin D1 was noted in 27% (119/440) of the primary breast carcinomas. Molecular analysis demonstrated that cyclin D1 was amplified in 30% (7/23) of the comedo DCIS, 22% (9/41) of the comedo DCIS and 32% (13/41) of the adjacent invasive ductal carcinomas, 30% (82/270) of the invasive ductal carcinomas, 27% (9/33) of the invasive lobular carcinomas, 19% (4/21) of the colloid carcinomas and 13% (2/15) of the medullary carcinomas. Cyclin D1 was amplified in 11% (2/19) of the invasive ductal carcinomas but not in the adjacent non-comedo DCIS lesions. Our observation showed that cyclin D1 was strongly positive in 61% (14/23) of the comedo subtype, 61% (11/18) of the non-comedo subtype, 59% (24/41) of the comedo DCIS and 63% (26/41) of the adjacent invasive ductal carcinomas, 53% (10/19) of the non-comedo DCIS and 58% (11/19) of the adjacent invasive lesions, 58% (157/270) of the invasive ductal carcinomas, 73% (24/33) of the invasive lobular carcinomas, 52% (11/21) of the colloid carcinomas and 27% (4/15) of the medullary carcinomas. A significant association was observed between in situ components and adjacent invasive lesions for cyclin D1 expression (p<0.05) and amplification (p<0.05). A significant relationship was noted between amplification of cyclin D1 and lymph node metastases (p<0.05) but not with histological grade (p>0.05), estrogen receptor status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). However, overexpression of cyclin D1 was statistically associated with well differentiated tumors (p<0.05) and estrogen receptor positivity (p<0.05). No relationship was seen with nodal status (p>0.05) and proliferation index (Ki-67 and PCNA) (p>0.05). These observations suggest that tumors positive for cyclin D1 protein may have features of good prognosis but amplification of cyclin D1 gene could be an indicator of tumors with poor prognostic features. Although majority of the Malaysian patients belong to younger age group (<50 years old), amplification and expression of cyclin D1 was not statistically associated with patient age (p>0.05). These observations indicate that amplification and up-regulation of cyclin D1 may be independent of patient age. Moreover, overexpression and amplification of cyclin D1 in preinvasive, preinvasive and adjacent invasive lesions, and invasive carcinomas suggest that the gene may play an important role in early and late stages of breast carcinogenesis.     

Minimal breast cancer: evaluation of histology and biological marker expression.

Ninety-eight minimal breast cancers (MBCs) diagnosed between 1975 and 1990, and all originally considered to be invasive were found, on review, to form three groups: (a) 28 predominantly invasive carcinomas < or = 10 mm ('predominant invasive'); (b) 48 predominantly ductal carcinoma in situ (DCIS) lesions with definite foci of invasion each < or = 10 mm ('predominant DCIS'); and (c) 22 DCIS without evidence of invasion ('pure DCIS'). Tumour histology and immunohistochemical expression of Ki-67, c-erbB2, p53, oestrogen receptor (ER), progesterone receptor (PR), and Bcl-2 were compared. The major finding was the contrasting features in the two invasive groups, with significant differences in their extent of invasion (P < 0.0001), tumour grade (P = 0.03), DCIS type (P = 0.008) and in marker expression. In the predominant invasive group, the infiltrative component was usually greater than 5 mm, low-grade and associated with well-differentiated DCIS. Expression of Ki-67, c-erbB2 and p53 was generally low, and that of ER, PR and Bcl-2 high. The predominant DCIS group in contrast had a much smaller, commonly high-grade, invasive component, usually with poorly differentiated DCIS and the reverse pattern of marker expression. Although not significant, survival of patients in the predominant invasive group was slightly better. These findings suggest that invasive MBCs should perhaps be treated as separate entities, in order to aid more appropriate selection of treatment.     

Clinical characteristics of different histologic types of breast cancer

Breast cancer is a heterogeneous disease, though little is known about some of its rarer forms, including certain histologic types. Using Surveillance, Epidemiology, and End Results Program data on 135 157 invasive breast cancer cases diagnosed from 1992 to 2001, relationships between nine histologic types of breast cancer and various tumour characteristics were assessed. Among women aged 50-89 years at diagnosis, lobular and ductal/lobular carcinoma cases were more likely to be diagnosed with stage III/IV, > or =5.0 cm, and node-positive tumours compared to ductal carcinoma cases. Mucinous, comedo, tubular, and medullary carcinomas were less likely to present at an advanced stage. Lobular, ductal/lobular, mucinous, tubular, and papillary carcinomas were less likely, and comedo, medullary, and inflammatory carcinomas were more likely to be oestrogen receptor (ER) negative/progesterone receptor (PR) negative and high grade (notably, 68.2% of medullary carcinomas were ER-/PR- vs 19.3% of ductal carcinomas). In general, similar differences were observed among women diagnosed at age 30-49 years. Inflammatory carcinomas are associated with more aggressive tumour phenotypes, and mucinous, tubular, and papillary tumours are associated with less aggressive phenotypes. The histologic types of breast cancer studied here differ greatly in their clinical presentations, and the differences in their hormone receptor profiles and grades point to their likely different aetiologies.     

Immunohistochemical analysis on biological markers in ductal carcinomain situ of the breast

BACKGROUND: The increasing use of mammographic screening has led to an increased detection of ductal carcinoma in situ (DCIS) of the breast. The detailed biological characteristics of DCIS and a new classification of DCIS based on these characteristics are needed. METHODS: Immunohistochemical studies were performed to assess the expression of c-erbB-2 (ErbB-2), estrogen receptor (ER), p53 and proliferative activity (Ki-67) in 65 patients with pure DCIS and 60 with invasive ductal carcinoma (IDC). We classified pure DCIS tumors using three classifications, the architectural, Nottingham, and Van Nuys classifications. RESULTS: ErbB-2, ER and p53 staining was positive in 34%, 66% and 21% of patients with DCIS, respectively, and 58%, 42% and 33% in patients with IDC, respectively. Ki-67 stained positively in 1.5% of patients with DCIS and 11.2% of patients with IDC. The comedo type showed a high rate of positive ErbB-2 and p53 staining. The cribriform and papillary types showed a high rate of positive ER staining. Under the Van Nuys classification, ErbB-2, p53 and Ki-67 expression were highest in the group with high nuclear grade and lowest in the group with non-high nuclear grade without necrosis. CONCLUSION: Although the biological markers of IDC tended to suggest aggressive behavior more so than those of DCIS, these differences were based on the histological sub-type, comedo or non-comedo. The Van Nuys classification best defined the subgroups of DCIS with a distinct expression pattern of biological markers, and the best candidates for breast-conserving surgery.     

Age-specific incidence rates of in situ breast carcinomas by histologic type, 1980 to 2001.

Incidence rates of ductal carcinoma in situ (DCIS) and lobular carcinoma in situ (LCIS) have increased rapidly over the past several decades largely due to the increased use of mammography. However, recent data from 1987 to 1999 indicate that invasive ductal carcinoma incidence rates have remained essentially constant, whereas rates of invasive lobular carcinoma have increased 65%, with greater increases observed among postmenopausal women. Data on recent trends in DCIS and LCIS incidence rates, particularly age-specific trends, are lacking. We evaluated trends in the incidence rates of DCIS overall, noncomedo DCIS, comedo DCIS, and LCIS using data from nine Surveillance, Epidemiology, and End Results cancer registries. DCIS incidence rates increased 7.2-fold [95% confidence interval (95% CI), 6.8-7.7] from 1980 to 2001, 1.8-fold (95% CI, 1.7-1.9) over the past 10 years (1992-2001), and 1.1-fold (95% CI, 1.0-1.2) over the past 5 years (1997-2001). The magnitudes of these increases were highest among women ages > or = 50 years. Furthermore, over the past 10- and 5-year periods, rates of noncomedo DCIS have generally increased across all age groups, whereas rates of comedo DCIS held constant or decreased. LCIS incidence rates increased 2.6-fold (95% CI, 2.3-2.9) from 1980 to 2001, 1.3-fold (95% CI, 1.2-1.5) over the past 10 years, and 1.1-fold (95% CI, 1.0-1.3) over the past 5 years. Similar to invasive lobular carcinoma, but unlike invasive ductal carcinoma, incidence rates of both DCIS and LCIS continue to increase in the United States primarily among older women. These trends present important public health and clinical challenges.     

Infiltrating ductal and lobular breast carcinomas are characterised by different interrelationships among markers related to angiogenesis and hormone dependence

To obtain a more integrated understanding of the different breast cancer phenotypes and to investigate whether bio-molecular profiles can distinguish between specific histotypes, we explored the interrelations among several biologic variables indicative of, or related to, hormone dependence, proliferation and apoptosis control, and angiogenesis in ductal and lobular carcinomas, the most common histotypes. Oestrogen and progesterone receptors, tumour proliferative activity, the expression of cyclin A, p16(ink4A), p27(kip1), p21(waf1), p53, bcl-2, and levels of vascular endothelial growth factor and hypoxia-inducible factor-1alpha (HIF-1alpha) were evaluated in 190 in ductal and 67 lobular carcinomas. Our findings support the hypothesis that in ductal and lobular carcinomas are two distinct, partially phenotypically unrelated entities, the latter being characterised by the presence of features indicative of differentiation such as oestrogen receptors, low proliferation and lack of p53 expression and associated with low vascular endothelial growth factor content compared to angiogenesis in ductal carcinomas. Conversely, no significant difference was found between lobular carcinomas and in ductal carcinomas considering the frequency distribution of PgR-positive cases, cyclin-dependent kinase inhibitors acting at the G1/S boundary, bcl-2 and HIF-1alpha protein expression. Although both generally defined as hormone responsive, in ductal and lobular carcinomas are also characterised by biologic patterns in which proteins related to hormone responsiveness, cell-cycle control, apoptosis and angiogenesis were differently associated. This finding suggests the need to refine breast cancer characterisation in order to provide detailed information about individual tumours, or subsets of tumours, that will help in defining optimal treatment approaches.     

p53 protein as a prognostic indicator in breast carcinoma: a comparison of four antibodies for immunohistochemistry.

We examined the reactivity of four p53-specific monoclonal antibodies--PAb 1801, p53-BP-12, D07 and CM1--on sections of formalin-fixed tissue collected from 245 breast carcinomas. Immunodetection of p53 varied between 37.6% and 46.6%. The greatest variation was observed among lobular carcinomas and low-grade tumors in which immunodetection varied between 8.3% and 27.3%. In contrast, immunodetection of p53 in invasive ductal carcinomas was subject to a lower degree of variability with between 40.6% and 49.7% of these tumours proving to be positive. In general, we found antibodies PAb 1801 and DO7 to be the most effective in immunolocalising p53. Immunodetection of p53 with each of the four antibodies was found to correlate strongly with tumour grade. In survival analysis, the results gained using antibody PAb 1801 proved to be of greatest statistical significance and to provide the strongest index of prognosis. A significant relationship was observed between immunodetection of p53 with each of the four antibodies and poor responsiveness to endocrine therapy. In addition, relationships were also observed between p53 immunostaining and tumour oestrogen receptor (ER) status as well as c-jun expression. We observed no correlation between abnormalities of the p53 and the Rb gene products or between elevated c-erbB-2 or epidermal growth factor receptor (EGFR) expression and immunodetection of p53.     

Evidence of significant apoptosis in poorly differentiated ductal carcinoma in situ of the breast.

Following breast-conserving surgery for ductal carcinoma in situ (DCIS), the presence of comedo necrosis reportedly predicts for higher rates of post-operative recurrence. To examine the role of programmed cell death (apoptosis) in the aetiology of the cell death described as comedo necrosis, we studied 58 DCIS samples, using light microscopy, for morphological evidence of apoptotic cell death. The percentage of apoptotic cells (apoptotic index, AI) was compared between DCIS with and without evidence of ''comedo necrosis'' and related to the immunohistochemical expression of the anti-apoptosis gene bcl-2, mitotic index (MI), the cellular proliferation antigen Ki67, nuclear grade and oestrogen receptor (ER) status. AI was significantly higher in DCIS samples displaying high-grade comedo necrosis than in low-grade non-comedo samples: median AI = 1.60% (range 0.84-2.89%) and 0.45% (0.1-1.31%) respectively (P < 0.001). Increasing nuclear grade correlated positively with AI (P < 0.001) and negatively with bcl-2 expression (P = 0.003). Bcl-2 correlated negatively with AI (P = 0.019) and strongly with ER immunoreactivity (P < 0.001). Cellular proliferation markers (MI and Ki67 immunostaining) correlated strongly with AI and were higher in comedo lesions and tumours of high nuclear grade (P < 0.001 in all cases). Thus, apoptosis contributes significantly to the cell death described in ER-negative, high-grade DCIS in which a high proliferative rate is associated with a high apoptotic rate. It is likely that dysregulation of proliferation/apoptosis control mechanisms accounts for the more malignant features typical of ER negative comedo DCIS.     

DNA methylation of RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist in in situ and invasive lobular breast carcinoma

Little is known about epigenetic silencing of genes by promoter hypermethylation in lobular breast cancers. The promoter methylation status of 5 cancer-related genes (RASSF1A, HIN-1, RAR-beta, Cyclin D2 and Twist) was evaluated in 2 types of lobular cancers, in situ (LCIS) and invasive lobular carcinomas (ILC) (n = 32), and compared to ductal in situ (DCIS) and invasive (IDC) breast cancers (n = 71). By using methylation-specific PCR (MSP), 100% of ILC and 69% of LCIS cases were found to have 1 or more hypermethylated genes among the panel of 5 genes (compared to 100% IDC and 95% of DCIS). Two or more hypermethylated genes were detected per tumor in 79% of invasive and 61% of in situ lobular carcinomas compared to 81% of IDC and 77% of DCIS. By contrast, DNA from nearly all normal reduction mammoplasty tissues (n = 8) was unmethylated for the 5 genes. The methylation profiles of lobular vs. ductal carcinomas with respect to RASSF1A, Cyclin D2, RARbeta, and Hin-1 genes were similar, suggesting that gene silencing by promoter hypermethylation is likely to be important in both groups of diseases. Distinctly different, Twist was hyper- methylated less often in ILC (16%, 3/19 cases) than in IDC (56%, 15/27 cases) (p = 0.01). These results suggest that these 2 types of tumors share many common methylation patterns and some molecular differences. Additional studies might lend further understanding into the etiology and clinical behavior of this tumor type.     

Bax protein expression in DCIS of the breast in relation to invasive ductal carcinoma and other molecular markers

This study describes the incidence of Bax protein expression in a series of 106 cases of breast cancer including 56 cases of ductal carcinoma in situ (DCIS) and 50 cases of invasive ductal carcinoma (IDC). Relationships of Bax expression to the histological grades of DCIS & IDC, and to the expression of Ki67, ER, p53, cerbB2 & Bcl2 are described. The expression of Bax, Ki67, ER, p53, cerbB2 and Bcl2 proteins is determined immunohistochemically. Cases were regarded positive for Bax, Bcl2 and cerbB2 when they showed either moderate or strong staining for these markers. The nuclear stains (Ki67, ER, and p53) were quantified in terms of percentage positive cells and cases for ER and p53 were considered positive when more than 10% cells were labelled. DCIS were graded histologically as well (n=18), intermediately (n=18), and poorly differentiated (n=20) Invasive ductal carcinoma was graded as grade I (well-differentiated) n=7, grade II (intermediate) n=24 and grade III (poorly differentiated) n=19. 65/106 cases (61%) were Bax positive including 37/56 (66%) of DCIS and 28/50 (56%) of IDC. Bax expression did not correlate to increasing histological grades of either DCIS or IDC. It did not correlate to Ki67, ER, p53 or cerbB2 but positive correlation was seen with Bcl2 (p=0.003). Bcl2 immunostaining displayed a negative correlation with increasing histological grades both of DCIS and IDC (p=0.026), (p=0.041) respectively. There was a trend of negative correlation of Bcl2 with Ki67 (p=0.062). It correlated positively with Bax (p=0.003) and ER (p<0.0001). Results suggest that the regulation of apoptosis is important in ductal carcinoma in situ of the breast as well as invasive ductal carcinomas. Bcl2 is associated with good prognostic markers in both DCIS and IDC, whereas the regulation of Bax is complex and does not necessarily correlate with mutant p53.     

Histological grade,p53, HER2 and hormone receptor status of synchronous bilateral breast carcinoma

BACKGROUND AND OBJECTIVES: Histological grade and tumor biology remain important predictors of the clinical behavior of breast carcinomas. We analyzed the clinicopathological characteristics and tumor biology with regard to histological grade (HG), p53, HER2 and hormone receptor status to address this question. PATIENTS AND METHODS: A consecutive series of 74 female synchronous bilateral breast carcinoma patients treated at the National Cancer Center Hospital were the primary source of these retrospective data. Clinicopathological background factors, histological grade and immunohistochemical staining for p53, HER2 and hormone receptor status, were analyzed. RESULTS: Of 148 synchronous bilateral tumors, 102 were invasive ductal carcinoma (IDC). The others included 24 pure or predominant ductal carcinoma in situ (DCIS), 5 spindle cell carcinomas, 16 invasive lobular carcinomas and 1 squamous cell carcinoma. 128 cases (128/148: 89%) were HG 1 (72/148: 49%) or HG 2 (56/148: 38%). The positivity rates for p53, HER2, estrogen receptor (ER) and progesterone receptor (PR) were 9%(14/148), 18%(26/148), 64%(95/148) and 64%(95/148), respectively. CONCLUSION: Our findings indicate that synchronous bilateral breast carcinomas showed a higher frequency of invasive lobular carcinoma, lower HG and higher rate of hormone receptor positivity than unilateral breast carcinomas.     

Genomic aberrations in normal tissue adjacent to HER2-amplified breast cancers: field cancerization or contaminating tumor cells?

Recent molecular data pointed towards the possibility of a stepwise dedifferentiation in a subgroup of invasive breast cancer (BC) cases. It was hypothesized that oestrogen receptor positive (ER+) grade 3 (G3) ductal invasive BCs are the end stage of a dedifferentiation process of luminal BC. A progression of luminal A towards luminal B BCs associated with a 'progression through grade' and an increased cell proliferation seemed the obvious explanation. In order to verify this hypothesis on a morphological and immunohistochemical level, we investigated 865 invasive BC cases. All cases were reviewed for the presence of intratumoural heterogeneity in grade of the invasive cancer and the presence of associated ductal carcinoma in situ (DCIS). With the use of tissue microarrays, the molecular subtype was determined and correlated with clinico-pathological features. In addition, all cases were stained for p21, p27, Ki-67, Cyclin D1, bcl-2, p53, and p16 and the results subjected to a biomathematical dependency analysis. The frequency of ER-positivity decreased with tumour size. The frequency of luminal A BC decreased as well, whereas the number of luminal B BCs remained constant. A gradual increase of the frequency of basal-like, HER2-driven and non-expressor BCs with tumour size was seen. In only 1 out of 865 BC cases, both a G1 and a G3 invasive cancer component was seen within the same BC. In two cases, a ductal invasive G1 carcinoma was associated with a poorly-differentiated DCIS. The frequency of columnar cell lesions was evenly distributed over ER+ and ER- ductal invasive G3 carcinomas. The biomathematical analysis gave striking hints against an obligate progression of BC trough grade. In conclusion, our results show that a morphological recognizable striking 'progression through grade' at least in its extreme form from G1 towards G3 is a very rare event in the natural course of invasive BC, including luminal BC.     

Loss of wild-type p53 and C-erbb2 amplification correlates with high-grade breast carcinomas

Breast cancer is the most common cancer in women in the western world. Two of the most frequently occuring chromosomal abnormalities in human breast carcinoma are the loss of p53 tumour suppressor gene function and the amplification of the c-erbB2 oncogene. Previous studies have demonstrated the role of p53 gene product in the maintenance of chromosomal stability and the correlation between c-erbB2 amplification and breast carcinogenesis. In this study we have examined the existence of a possible correlation between these genetic alterations in a panel of 83 malignant breast tumours (69 adeno and 14 lobular carcinomas). The status of a related gene, c-erbB3, was also examined. With the aid of microsattelite marker TP53CA loss of heterozygosity (LOH) was detected in the p53 locus in 49% of the tumours. Histochemical analysis of 64 of these tumours with the p53 antibody CM1 demonstrated staining, indicative of an elevated steady-state level of p53 protein in 23 rumours (36%). Amplification of the c-erbB2 gene was detected in 20 of 75 tumours analysed (27%). In the tumours with c-erbB2 amplification 12 also had p53 LOH. In at least another 2 tumours there was increased p53 protein level but no LOH. Therefore in 75% of the tumours with c-erbB2 amplification there was evidence of loss of normal p53 function. There was no evidence of c-erbB3 amplification in any of the 75 rumours analysed. The data presented demonstrates a strong correlation between the loss of p53 and tumour grade (p<0.00545), and a strong association between c-erbB2, but not c-erbB3, amplification and loss of p53 (p<0.0170).     

The expression of products of oncogens c-erbB2 and EGFR and proliferating antigens Ki67 and PCNA in primary invasive ductal cancer of female breast

The aim of the study was to examine the consecutive series of primary ductal invasive tumours and find out: a) the expression of some biological cellular parameters as proliferating antigens Ki67 and PCNA and products of gene EGFR, erbB2; b) correlation between the levels of expression of those factors and classical prognostic factors, such as diameter of tumour, status of axillary lymph nodes, status of steroids receptors, the degree of histological differentiation. We found that: 1. The presence of the expression of oncoproteins c-erbB2 and EGFR, high index IP PCNA, Ki67 and low levels of steroids receptors correlates with high histological malignancy (Bloom III0); 2. The lack of expression of oncoproteins c-erbB2, EGFR and low index IP PCNA, Ki67 correlates with high levels of steroids receptors; 3. The estimation of high levels of index IP PCNA, IP Ki67 can be helpful for separate tumours of high proliferating activity; 4. The expression of oncoprotein c-erbB2 and EGFR does not correlate with the diameter of tumour as well as with the involvement of axillary lymph nodes. It seems that the estimation of proliferating antigens together with the expression of oncoproteins might have greater prognostic value than the estimation of one of these factors.     

P53 and C-erbb-2 alterations in in-situ and invasive ductal breast carcinomas - a genetic and immunohistochemical analysis

p53 mutations, c-erbB-2 amplifications and expression of the related proteins were evaluated in a panel of ductal breast carcinomas selected on the basis of their invasive component. The tumors comprised: 8 ductal carcinomas in situ (DCIS); 8 carcinomas with a minimal (less than 20%) invasive component, hereafter referred to as DCIC (<20%); 13 carcinomas with 20%-50% invasiveness, DCIC (20-50%), and 48 infiltrating carcinomas with more than 50% invasive component, DCIC (>50%). Tumors were further subdivided into large pleomorphic cell type or small regular cell type. A strong association was present between p53 gene mutations and p53 protein overexpression (p<0.001) as well as between amplification of the c-erbB-2 gene and expression of its protein product (p=0.006). p53 aberrations (gene mutation and/or protein overexpression) were observed in 1 (12%) of 8 DCIS, 1 (11%) of 9 DCIC (<20%), 3 (23%) of 13 DCIC (20%-50%), and 13 (28%) of 47 DCIC (>50%). Amplification and/or overexpression of c-erbB-2 were found in 30 (39%) of the 77 breast carcinomas analyzed and were more frequent in DCIC (<20%) and in DCIC (20%-50%) (56% and 46% respectively) than in DCIS or DCIC (>50%) (12% and 38% respectively). Irrespective of the presence of invasion, tumors with p53 or c-erbB-2 alterations showed more frequently large cells with pleomorphic nuclei, (for p53, p=0.027; for c-erbB-2, p=0.014). Our data suggest that p53 and c-erbB-2 alerations may occur in the earliest recognized phase of breast cancer and may be important in the evolution of small cell to large cell mammary carcinoma during tumor progression.     

p21WAF1 immunohistochemical expression in breast carcinoma: correlations with clinicopathological data, oestrogen receptor status, MIB1 expression, p53 gene and protein alterations and relapse-free survival.

p21 protein (p21) inhibitor of cyclin-dependent kinases is a critical downstream effector in the p53-specific pathway of growth control. p21 can also be induced by p53-independent pathways in relation to terminal differentiation. We investigated p21 immunoreactivity in normal breast and in 91 breast carcinomas [three in situ ductal carcinomas (DCIS) with microinfiltration and 88 infiltrating carcinomas, 17 of which with an associated DCIS; 57 node negative and 34 node positive] with long-term follow-up (median = 58 months). Seven additional breast carcinomas with known p53 gene mutations were investigated. In normal breast p21 expression was seen in the nuclei of rare luminal cells of acinar structures, and in occasional myoepithelial cells. Poorly differentiated DCIS showed high p21 expression, whereas well-differentiated DCIS tumours showed few p21-reactive cells. p21 was seen in 82 (90%) infiltrating tumours; staining was heterogeneous; the percentage of reactive nuclei ranged from 1% to 35%. High p21 expression (more than 10% of reactive cells) was seen in 24 (26%) cases, and was associated with high tumour grade (P = 0.032); no associations were seen with tumour size, metastases, oestrogen receptor status, MIB1 expression and p53 expression. p21 expression in cases with p53 gene mutations was low in six cases and high in one. High p21 expression was associated with short relapse-free survival (P = 0.003).     

E-cadherin relates to EGFR expression and lymph node metastasis in primary breast carcinoma.

Expression of the calcium-dependent cell-cell adhesion molecule E-cadherin has been examined in 187 primary breast carcinomas using an immunohistochemical technique. The pattern and extent of reactivity has been correlated with clinicopathological data including tumour type, grade and lymph node status and with other prognostic parameters including oestrogen receptor (ER) status, expression of c-erbB-2, pS2 protein and epidermal growth factor receptor (EGFR). Two patterns of E-cadherin staining were observed in carcinomas, membrane reactivity and a diffuse cytoplasmic staining. A marked difference in expression of E-cadherin was observed between infiltrating lobular carcinomas (ILC) and infiltrating ductal carcinomas (IDC), the former showing complete loss of membrane staining, whereas 93% of IDC retained some level of expression. In IDC reactivity was not related to tumour grade but there was a significant association between reduced membrane levels of E-cadherin and the presence of lymph node metastasis, and a highly significant correlation between the presence of cytoplasmic E-cadherin and metastasis. A significant relationship was also demonstrated between reduced E-cadherin reactivity and expression of EGFR. These findings emphasise the complexity of control of E-cadherin in breast carcinomas and provide evidence of a link between membrane signalling pathways and modulation of E-cadherin expression.     

EGFR与HER-2在不同分子类型乳腺癌中的表达及其相关性分析

目的：探讨EGFR和HER-2在不同分子类型乳腺癌组织中的表达及其相关性。方法：回顾性分析2015年1月—2020年3月在邯郸市中心医院行手术治疗的乳腺癌患者资料650例(其中浸润性导管癌600例，浸润性小叶癌50例)及乳腺纤维腺瘤30例，应用免疫组织化学(IHC)方法对手术切除标本进行EGFR和HER-2蛋白表达检测，采用χ²检验及Spearman相关分析对数据进行统计学分析。结果：EGFR在乳腺浸润性导管癌中表达阳性率为48.7%，显著高于浸润性小叶癌(24.0%)及纤维腺瘤(16.7%)(P<0.01)。HER-2在乳腺浸润性导管癌中表达阳性率为27.8%，显著高于浸润性小叶癌(8.0%)及纤维腺瘤(6.7%)(P=0.002)。乳腺浸润性导管癌与浸润性小叶癌中，EGFR阳性率与HER-2评分等级呈正相关(r=1.000，P<0.05)，且EGFR阳性率与HER-2阳性表达呈正相关(r=1.000，P<0.05)。EGFR阳性率在HER-2过表达型与三阴型乳腺癌组织中显著高于Luminal A型和Luminal B型，且Luminal B中HER-2阳性显著高于HER-2阴性亚型(P<0.001)。结论：EGFR、HER-2阳性率在乳腺浸润性导管癌显著升高，且EGFR阳性率与HER-2的评分等级及阳性表达率均呈正相关，EGFR在HER-2过表达型与三阴型乳腺癌组织中显著升高，为进一步研究HER-2阳性乳腺癌及三阴型乳腺癌的靶向药物治疗提供线索及理论依据。     

The poor responsiveness of infiltrating lobular breast carcinomas to neoadjuvant chemotherapy can be explained by their biological profile

The aim of this study was to determine the chemosensitivity of infiltrating lobular breast carcinoma (ILC) in comparison with infiltrating ductal carcinoma (IDC). Between 1987 and 1995, 457 patients with invasive T2>3 cm-T4 breast carcinomas were treated with primary chemotherapy (CT), surgery, radiation therapy. Clinical response, the possibility of breast preservation, pathological response and survival were evaluated according to the histological type. In order to evaluate the biological differences between ILC and IDC patients and their implication with regard to tumour chemosensitivity, additional immunohistochemical stainings (oestrogen receptor (ER), Bcl2, p53, c-erbB-2 and Ki67) were performed on 129 pretherapeutical specimens. 38 (8.3%) ILC were diagnosed by core needle biopsy before CT. ILC was an independent predictor of a poor clinical response (P=0.02) and ineligibility for breast-conserving surgery after neoadjuvant chemotherapy (P=0.03). Histological and biological factors predicting a poor response to CT (histological grade, ER, Ki67 and p53 status) were more frequent in ILC than in IDC patients. After a median follow-up of 98 months (range: 3-166), the low chemosensitivity of ILC did not result in a survival disadvantage. Our results demonstrate that ILC achieved a lower response to CT than IDC because of their immunohistochemical profile. Preoperative CT did not allow a high rate of conservative treatment for ILC and therefore the use of neoadjuvant CT for ILC patients should be questioned.