Journal of Pathology and Translational Medicine

Review

HER2 status in breast cancer: changes in guidelines and complicating factors for interpretation: Soomin Ahn, Ji Won Woo, Kyoungyul Lee, So Yeon Park; J Pathol Transl Med. 2020;54(1):34-44. Published online November 6, 2019; DOI: https://doi.org/10.4132/jptm.2019.11.03

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Human epidermal growth factor receptor 2 (HER2) protein overexpression and/or HER2 gene amplification is found in about 20% of invasive breast cancers. It is a sole predictive marker for treatment benefits from HER2 targeted therapy and thus, HER2 testing is a routine practice for newly diagnosed breast cancer in pathology. Currently, HER2 immunohistochemistry (IHC) is used for a screening test, and in situ hybridization is used as a confirmation test for HER2 IHC equivocal cases. Since the American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines on HER2 testing was first released in 2007, it has been updated to provide clear instructions for HER2 testing and accurate determination of HER2 status in breast cancer. During HER2 interpretation, some pitfalls such as intratumoral HER2 heterogeneity and increase in chromosome enumeration probe 17 signals may lead to inaccurate assessment of HER2 status. Moreover, HER2 status can be altered after neoadjuvant chemotherapy or during metastatic progression, due to biologic or methodologic issues. This review addresses recent updates of ASCO/CAP guidelines and factors complicating in the interpretation of HER2 status in breast cancers.

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Original Articles

Metaplastic Squamous Carcinoma of the Breast: Clinicopathologic Analysis of 17 Cases.: Sun Ah Lee, Kyung Eun Lee, Byung In Moon, Woon Sup Han, Sun Hee Sung; Korean J Pathol. 2009;43(1):20-25.; DOI: https://doi.org/10.4132/KoreanJPathol.2009.43.1.20

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Abstract PDF

BACKGROUND
Squamous cell carcinoma of the breast is very rare and it is considered to arise from metaplastic change of ductal carcinoma. Metaplastic squamous cell carcinoma (MSC) of the breast includes pure squamous cell carcinoma, metaplastic adenosquamous carcinoma and low grade adenosquamous carcinoma. Most of the cases of MSC of the breast were reported to have lymph node metastasis and this has a worse prognosis than that of conventional invasive ductal carcinoma.
METHODS
We collected 17 cases of MSC of the breast from 1,173 cases of breast cancer and analyzed the clinicopathological characteristics.
RESULTS
The age range was 31 to 69 years (mean age: 47.2). The mean tumor size was 3.6 cm. Twelve cases (70.6%) had a negative nodal status. The majority of the cases were of a high nuclear grade (grade III: 76.5%), and a high histologic grade (grade III: 88.2%). All the cases had no amplification of HER2, and they were negative for hormonal receptors, except for 2 cases with weak positivity. All the cases showed positivity for EGFR (3+: 14 cases, 1+: 3 cases). Clinical relapse was found in 3 patients on follow up and two of them expired due to lung and bone metastasis.
CONCLUSIONS
MSC is associated with high nuclear and histologic grades, a high EGFR expression and they are triple negative for ER, PR, and HER2. The EGFR immunopositivity of MSC suggests a basal-like subtype.

Citations

Citations to this article as recorded by

Eccrine ductal and acrosyringeal metaplasia in breast carcinomas: report of eight cases
Tibor Tot
Virchows Archiv.2019; 474(3): 383. CrossRef
Significance of Foxp3 Positive Regulatory T Cell and Tumor Infiltrating T Lymphocyte in Triple Negative Breast Cancer
Hanna Kang, Harin Cheong, Min Sun Cho, Heasoo Koo, Woon Sup Han, Kyung Eun Lee, Byung In Moon, Sun Hee Sung
The Korean Journal of Pathology.2011; 45(1): 53. CrossRef

The Effect of Tamoxifen and Pentosan Polysulfate on the Microvessel Density and Cell Proliferation of Dimethylbenzanthracene-Induced Rat Mammary Carcinoma.: Chan Heun Park, Zhe Piao, Kwang Gil Lee; Korean J Pathol. 1996;30(2):94-105.

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Abstract PDF: Antiestrogen tamoxifen (TMX) is thought to elicit its therapeutic effect by competing with endogenous estrogens for the estrogen receptor. Several more recent studies asserted that the antitumor effect of TMX is not due solely to the inhibition of estrogen receptor-mediated action, but due partly to its capacity to inhibit angiogenesis and impair neovascularization. Despite extensive research and clinical experience with this drug, its exact mode of action in inducing tumor regression is still not clear. The present study is aimed toward the investigation of the effects of TMX on dimethylbenzanthracene- induced rat mammary carcinomas with respect to the tumor response to the drugs, histological changes, cell proliferative acitivity and angiogenesis inhibition, and if TMX has antiangiogenic action, to compare it with that of pentosan polysulfate (PPS), an already known antiangiogenic substance. Female Sprague-Dawley rats, aged 50 days, were divided into normal control, test control (tumor induction by dimethylbenzanthracene), TMX (TMX administration after tumor induction), and PPS (PPS administration after tumor induction) groups. Tumor response to the drug administration was classified according to changes of tumor volume as follows; complete response (CR), partial response (PR), no response (NR), and progressive disease (PD). The response rate of rat mammary carcinomas to the drug administration was significantly higher (p<0.05) in the TMX and PPS groups as compared with the test control group. There was, however, no statistical significance between the TMX and PPS groups. Necrosis was considerably frequent in tumors of the TMX and PPS groups. Hyaline change of the stroma was strikingly more common and marked in the TMX group and it was associated with atrophy of epithelial cells of the tumor glands. Proliferating cell nuclear antigen (PCNA)- labeling index of the tumors was significantly higher (p<0.05) in the tumors with NR and PD of the TMX group when compared with those with PR of the same group, which suggested a higher cell proliferative activity in these response groups. In the PPS group, however, there was no significant difference in PCNA index according to response. Microvessel density of the tumors was significantly lower (p<0.05) in the PPS group as compared with the test control and TMX groups and it was not related with response. The TMX group, however, did not show any significant difference in microvessel density when compared with the test control group. Microvessel density was significantly higher (p<0.05) in tumors with PD than those with PR in all 3 groups, which suggested a positive relation of increase in tumor size and angiogenesis. Based on these results it is thought that TMX and PPS inhibit growth of chemically-induced rat mammary carcinomas. It seems that the antitumor action of PPS is related with its antiangiogenic capability, but that of TMX does not have a relationship with angiogenenesis inhibition.

Analysis of Estrogen and Progesterone Receptors in Breast Carcinoma: Comparison of immunocytochemical assay with biochemical dextran-coated charcoal assay.: Ill Hyang Ko, Kyeong Mee Park; Korean J Pathol. 1996;30(3):228-237.

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Abstract PDF: Estrogen receptor(ER) is a soluble form of hormone receptor protein which is located in the nucleus and cytoplasm of a cell is found in 60% of cases of the cells of breast carcinoma. Fifty to sixty percent of ER positive breast carcinoma responds to antihormone therapy wheres the response rate is only 5% in ER negative tumors. Currently, the ER assay has become a standard index in the management and prediction of the prognosis of advanced breast carcinoma. Semiquantitative biochemical assay, dextran-coated charcol(DCC) assay, to measure ER from fresh tissue was first developed by Korenman in 1970 using isotope-labled ertradiol, has been widely utilized. In 1978, Kurzon newly developed immunocytochemical assay(ICA) employing monoclonal antibody against those hormone receptors to detect intracellular localization of ER and progesterone receptor (PR). The results of the assay have been reported by many investigators thereafter. The purpose of this study was to evaluate the hormonal receptors with a monoclonal antibody using an immunoperoxidase procedure to detect both estrogen and progesterone receptors (ER-immunocytochemical assay:ER-ICA and PR-immunocytochemical assay:PR-ICA) in 59 cases of paraffin embedded sections from formalin-fixed and routinely processed breast carcinoma tissue. Concomitantly, fine-needle aspiration biopsy cytology of the breast cancer from 29 women were assayed for ER/PR receptors. Results were compared with quantitative biochemical values determined from dextran-coated charcoal(DCC) assay on the fresh tumor tissue obtained subsequently from the surgery. ER-ICA showed positive result in 22 out of 36 DCC-positive cases(sensitivity, 61.1%) and negative in 23 out of 23 DCC-negative cases (specificity, 100.0%). PR-ICA was positive in 33 out of 35 DCC-positive cases(sensitivity, 94.3%) and negative in 16 out of 24 DCC-negative cases(specificity, 66.7%). The value of ER-ICA or PR-ICA positivity were roughly correlated with the concentration of ER/PR receptors analyzed by DCC method. The results of both methods were correlated with the nuclear grade of the tumor(ICA:p=0.002, DCC: p=0.015) but were not correlated with histologic grade(ICA: p=0.323, DCC: p=0.0164). ER-ICA positivity was correlated with lower incidence of axillary node metastasis (p=0.021) but no significant correlation between PR-ICA positivity and node metastasis(p=0.171). Both ER/PR-ICA positivity were not correlated with age(p=0.924) and tumor size(p=0.663). The score of ICA particularly ER was proportional to DCC level(ER: r=0.5, p=0.000, PR: r=0.2, p=0.000). ICA concordance with DCC of ER and PR were 76.3% and 83.1%, respectively. The concordance of PR-ICA and DCC was proportional but was statistically less significant. In aspiration biopsy cytology the concordance of ER/PR-ICA and DCC were 72.4% and 65.5%, respectively. Immunocytochemical staining to identify ER/PR receptors from the tissue of breast carcinoma would be tested as a mean to substitute for the conventional DCC method.

Case Report

Secretory Carcinoma of the Breast: A case report.: Kyu Rae Kim, Jung Hyun Yang, Yeon Lim Seo, Howe Jung Ree; Korean J Pathol. 1996;30(4):347-350.

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Abstract PDF: We report a case of secretory carcinoma with axillary lymph node metastasis in a 21-year old woman. She was aware of a mass in her breast for 10 years and noticed a rapid growth of the preexisting mass during the last years. Histologically, the tumor was composed of micropapillary and microcystic or cribriform glandular structures which contained eosinophilic, mucinous, intraluminal secretions. The center had a dense hyalinized strama with a solid infiltrative growth of tumor cells with intracytoplasmic secretory vacuoles at the periphery. In addition, marked intraductal papillary epithelial proliferations were present at the superficial portions of the tumor near the nipple. Prognostic factors and their relationship to juvenile papillomatosis are discussed with a review of the literature.

Original Articles

Tumor Angiogenesis and Cathepsin-D Expression in Invasive Ductal Carcinoma of the Breast.: Young Gyung Bae, Dae Hong Suh, Dong Sug Kim, Soo Jung Lee; Korean J Pathol. 1997;31(8):735-744.

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Abstract PDF: This study was conducted to assess the prognostic value of tumor angiogenesis and Cathepsin-D in breast carcinoma, by correlating them with other clinicopathologic prognostic factors. In order to estimate microvessels within the tumor, an immunohistochemical method using monoclonal antibodies for factor VIII-related antigens (DAKO-vWf, F8/86) was used, and they were counted (perx200 field) in the most active areas of neovascularization. For the expression of Cathepsin-D, an immunohistochemical method using monoclonal antibodies (Novocastra, NCL-CDm) was performed. The microvessel count ranged from 8 to 346 per x200 field and the mean (+/-SD) was 72.46+/-54.96. The microvessel count was correlated with the estrogen receptor status, and it was also correlated with the tumor size when it was graded into four groups (1-33, 34-67, 68-100, >100), but was not correlated with other clinicopathologic parameters. Cathepsin-D was expressed in 40% (46/115) of the cases, but it was statistically correlated with the tumor size only. In conclusion, the expression of Cathepsin D and the degree of angiogenesis in breast cancer showed a correlation with the tumor size only. Therefore, they do not appear to be good prognostic parameters, according to the present study.

Expression of the pS2 Protein and Its Relation with Estrogen and Progesterone Receptor in Breast Cancer.: Eun Deok Chang, Chung Soo Chun; Korean J Pathol. 1998;32(3):169-173.

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Abstract PDF: Expression of the pS2 protein in breast carcinoma is a useful guide to evaluate the prognosis and response to tamoxifen. The pS2 protein is an estrogen-regulated 60 amino acid protein which was originally discovered following the screening of cDNA libraries in MCF-7 breast carcinoma cells and is induced through estrogen-dependent transcription of the pS2 gene. The presence of the pS2 protein in breast cancer is considered as valuable as the receptor status, or even more so, in predicting the response to hormonal therapy. We have investigated the pS2 protein expression in 62 cases of primary breast cancer in order to know the relationship between the expression rate of the pS2 protein and hormonal receptor status using immunohistochemical procedures on formalin-fixed and paraffin-embedded tissues. Concomitantly, both the estrogen receptors (ER) and progesterone receptors (PR) were examined using the immunohistochemical technique. Positive staining for the pS2 was seen in forty-nine cases (79%) of the tumors. Forty three cases (88%) of the pS2 positive tumors were ER positive and forty one cases (84%) of the pS2 positive tumors were PR positive ; forty six cases (93%) of pS2 positive tumors were positive for ER and/or PR. The pS2 status correlated significantly with the ER (p<0.0001) and PR (p<0.001). The results reveal a close association between the pS2 protein and either or both the ER and PR status.

The Expression of p53, c-erbB-2 and nm23 Proteins in Breast Cancer.: Kyo Young Lee, Yong Goo Kim, Young Shin Kim, Kyung Ja Han, Chang Suk Kang, Jean A Kim, Won Il Kim, Sang In Shim; Korean J Pathol. 1999;33(2):88-95.

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Abstract: Recently, p53, c-erbB-2 and nm23 proteins have been studied in breast cancer. The expression of p53 protein indicates the mutation of p53 gene known as a tumor supressor gene, and c-erbB-2 gene amplification has been considered an indicator of poor prognosis and nm23 a metastsis suppressor gene. In order to elucidate the roles and relations of these proteins in the develpoment, progression and metastasis in breast cancer, we studied 89 cases of invasive breast cancer and 32 cases of lymph node metastasis for the expression of p53, c-erbB-2 and nm23 proteins using an immunohistochemical method. The results were as follows: 1) The expression rates of p53, c-erbB-2, and nm23 proteins in breast cancer were 40.4%, 34.8% and 55.1%, respectively. Co-expression of p53 protein and c-erbB-2 protein was found in 20.2% of cases, showing the highest incidence in poorly differentiated type (40%). 2) p53 protein expression was increased in poorly differentiated type but was not statistically significant. On the other hand, the expression of nm23 protein was decreased in poorly differentiated type, which was statistically significant (p<0.05). 3) The correlation of p53 protein expression with c-erbB-2 protein expression was statistically significant (p<0.05) but that with nm23 protein was not. 4) In the cases with lymph node metastasis, discordant expression of p53, c-erbB-2 and nm23 proteins between primary tumor and the lymph node metastatic tumor was found in 9.4%, 3.1% and 18.8% of cases, respectively. The above results suggest that overexpression of p53 and c-erbB-2 proteins and downregulation of nm23 protein are associated with the tumor progression in the breast cancer.

Analyses of Genetic Alterations in Breast Cancers by Comparative Genomic Hybridization.: Jin Man Kim, Young Mi Jeon, Young Hyeh Ko, Kyu Sang Song, Howe J Ree, Joo Seob Keum, Jae Hyuk Lee, Sun Hoe Koo; Korean J Pathol. 1999;33(8):603-613.

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Abstract PDF: Transformation and progression of breast cancer are thought to be caused by an accumulation of complex genetic alterations, but little is known about specific changes. In this study, the author has undertaken a genome-wide screening to detect genetic changes in 20 cases of breast cancer among Koreans, including 16 infiltrating ductal carcinomas, 2 medullary carcinomas, 1 invasive lobular carcinoma, and 1 borderline phyllodes tumor. Comparative genomic hybridization (CGH) was used to screen for DNA sequence gains and losses across all human chromosomes. Simultaneous immunohistochemical staining for c-erbB-2 (Her-2/neu), c-myc, cyclin D1, and p53 protein was done to make comparisons with nuclear grade and that with CGH results. Biotin-labeled tumor DNA and digoxigenin-labeled normal DNA were hybridized to normal metaphase cells. The fluorescence signals were captured by fluorescence microscope after detection by avidin-FITC and anti-digoxigenin rhodamine. Then, the ratio of fluorescence was calculated by an image analyzer. The immunohistochemical staining was done in paraffin-embedded tissue with an LSAB kit and avidin-biotin complex (ABC) method. The CGH results showed gains on chromosomes 8q (40%), 1q (30%), 17q (15%), 20q (15%), 18q (15%), 5p (15%), and 13q (15%). Deletions were on chromosomes 17p (45%) and 22q (20%). High-level amplifications (green/red ratio >1.5) were noted on chromosomes 1p31, 1q, 3q25-qter, 5p, 7q31-qter, 8q, 9p22-qter, 10p, 11p, 11q22-qter, 12p, 12q24, 14q21-qter, 15q23-qter, 17q, 18p, 18q12-qter, 20p, and 20q. By comparison with infiltrating ductal carcinoma, the two medullary carcinomas showed high-level amplification on chromosomes 1p31, 1q, 8q, 10p, 11p and 12p. c-erbB-2, c-myc, cyclin D1, and p53 protein expression was immunohistochemically detected in 9 of 20 (45%), 8 of 20 (40%), 10 of 20 (50%), and 13 of 20 (65%), respectively. The results indicate that the amplification on chromosome 8q, 1q and the deletions on chromosomes 17p and 22q are the most frequent genetic alterations in breast cancers among Koreans. The results reveal a different pattern of genetic alteration from previous studies. The CGH results were not correlated with the immunohistochemical profiles. The amplification pattern of medullary carcinomas was quite different from the pattern of infiltrating ductal carcinomas. The CGH was thought to be very useful in the screening of genetic alterations of solid tumors.

Correlation of Expression of CD44, p53 and bcl-2 Protein, DNA Ploidy Pattern, and Clinicopathologic Prognostic Factors in Invasive Ductal Carcinoma of the Breast.: Mi Ja Lee, Ho Jong Jeon, Kweon Cheon Kim; Korean J Pathol. 1999;33(12):1152-1162.

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Abstract PDF: In this study of 64 cases of breast cancer with a clinical follow-up period of more than 5 years, several prognostic factors were evaluated. The purpose of this study was to determine whether any one parameter or group of parameters serves as adequate predictors of tumor behavior and patient's prognosis. Several prognostic factors included clinicopathological variables (patient's age, histologic grade, status of lymph node (LN) metastasis, and tumor size), expression of estrogen receptor (ER), progesterone receptor (PR), p53, bcl-2 and CD44 by immunohistochemistry, and DNA ploidy pattern. The results showed that the expression of ER and PR had a significant inverse correlation with the histologic grade (ER, p=0.05; PR, p<0.05). The expression of p53 protein showed a significant relationship with high histologic grade of tumor (p<0.05). The expression of bcl-2 protein was preferably seen in low histologic grade of tumor (p<0.05) and significantly associated with ER positive or PR positive tumors (ER, p<0.05; PR, p<0.05). This results suggest that bcl-2 protein might play significant roles in ER and PR. The CD44 expression showed a significant relationship with tumor size (p<0.05). The large size and aneuploidy pattern of tumor had a tendency to be associated with shorter patient survival. Cox's multivariate analysis showed that overall survival was affected by LN metastasis because of the shorter survival in patients with LN metastasis. In conclusion, tumor size, DNA ploidy pattern, and LN metastasis were themselves significant predictors of breast cancer survival rate.

Significance of c-kit and COX-2 Expression in Breast Tissue.: Eun Kyung Kim, Won Mi Lee, Jong Eun Joo, Sook Kyung Ko; Korean J Pathol. 2008;42(3):157-161.

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Abstract PDF: BACKGROUND
The proto-oncogene c-kit encodes a transmembrane tyrosine kinase growth factor receptor. Studies have shown that c-kit is highly expressed in normal breast epithelium, but expression is decreased in primary breast cancer. Cyclooxygenase-2 (COX-2) is an inducible enzyme that converts arachidonic acid to prostaglandins. Expression of COX-2 has been reported in malignant tumors including breast cancer. We evaluated the expression of c-kit and COX-2 in benign and malignant lesions of the breast to assess the roles of these proteins in cancer initiation and progression.
METHODS
We characterized 20 benign lesions, 20 intraductal carcinomas and 70 invasive breast carcinomas. Immunohistochemical staining for c-kit and COX-2 was performed.
RESULTS
Expression of c-kit was detected in 75% of the benign breast lesions, 40% of the intraductal carcinomas and 10% of the invasive carcinomas. COX-2 expression was observed in 80% of the benign lesions, 70% of the intraductal carcinomas and 52% of the invasive carcinomas. Expression of c-kit was significantly correlated with tumor size (p=0.02). COX-2 expression was significantly correlated with negative expression of estrogen receptor and progesterone receptor (p=0.02, p=0.04), Her-2/neu expression (p=0.008) and the high proliferation index (p=0.0002).
CONCLUSIONS
Our results suggest that c-kit and COX-2 might be involved in malignant transformation of the mammary epithelium and tumor progression. It is suggested that c-kit and COX-2 can be used as predictive markers and therapeutic targets.

Reduced Expression of Claudin-7 Correlates with Invasiveness and Nuclear Grade of Breast Carcinomas.: Sang Hee Seok, Su Hwan Kang, Soo Jung Lee, Tae Yoon Hwang, Young Kyung Bae; Korean J Pathol. 2007;41(3):158-164.

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Abstract PDF: Background
: Claudins are important components of the tight junctions in the intercellular barriers and cell polarity. Among them, claudin-7 is down-regulated in breast cancers compared with the normal breast epithelium. The aim of this study was to determine the expression pattern and prognostic value of claudin-7 in breast carcinomas.
Methods
: Claudin-7 expression was evaluated immunohistochemically in 42 cases of ductal carcinoma in situ (DCIS) and in 142 cases of invasive breast carcinoma (IBC) using a tissue microarray (TMA).
Results
: Claudin- 7 was strongly expressed in the normal luminal epithelial cells in the breast lobule. The level of claudin-7 expression was significantly lower or absent in 45.2% (19/42) of DCIS and 72.5% (103/142) of IBC. A loss or reduced expression of claudin-7 correlated with the invasiveness (p=0.001) of breast carcinomas and a high nuclear grade (p=0.013) in IBC.
Conclusion
Claudin-7 is an important tight junction protein in the breast and a loss of expression may assist in the dissociation and invasion of tumor cells.

Subcellular Localization of p27(kip1) in Breast Cancer and Its Prognostic Significance.: Sook Hee Hong, Dae Choel Kim, Se Heon Cho, Young Seoub Hong; Korean J Pathol. 2006;40(3):185-192.

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Abstract PDF: BACKGROUND
p27 is a member of the cyclin-dependent kinase (CDK) inhibitors that arrest the progression of the cell cycle; thus, it acts as a tumor suppressor gene. The loss or decrease of p27 protein is frequently seen and this has an independent prognostic potential for many human cancers. p27 is functionally inactivated through accelerated proteolysis and cytoplasmic sequestration. Cytoplasmic mislocalization of p27 by abnormal phosphorylation in the tumor cells doesn't allow it to bind and inhibit nuclear cyclin/CDK targets.
METHODS
We examined the p27 protein expression in 86 cases of invasive ductal carcinoma of the breast via immunohistochemical staining to evaluate the subcellular localization of p27 and its relationship with the clinicopathologic features and the prognostic factors.
RESULTS
The nuclear expression of p27 was noted in 48.9% of the tumors, a combined nuclear and cytoplasmic expression was noted in 20.9%, a cytoplasmic expression was noted in 12.8%, and a negative expression was noted in 17.4%. The decreased nuclear expression and/or cytoplasmic mislocalization of p27 were statistically correlated with the nuclear grade (p=0.001), histologic grade (p=0.036), tumor size (p=0.033), lymph node metastasis (p=0.043), ER (p=0.001), and PR (p=0.001) status, while they were not correlated with patient age, stage, HER2, p53, and Ki67.
CONCLUSIONS
The breast tumors showing both decreased nuclear expression and cytoplasmic mislocalization of p27 are associated with a deranged cell cycle via functional inactivation and also with poor prognostic factors. It is expected that p27 can be a promising anticancer target molecule for the treatment of breast cancer.

Expression of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 in Human Breast Cancers.: Dong Hoon Kim, Chan Kum Park, Ho Jung Lee, Won Mi Lee, Eun Kyung Kim, Jong Eun Joo; Korean J Pathol. 2005;39(6):391-400.

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Abstract PDF: BACKGROUND
Cell cycle progression is governed by cell cycle regulators and inhibitors such as the cyclin dependent kinases (CDK), p27(Kip1), p21(WAF1/Cip1) and p53. The purpose of this study was to correlate expressions of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53 with the various clinicopathologic prognostic parameters of human breast cancers.
METHODS
The paraffin-embedded tissue sections from 102 patients with human breast carcinomas were examined by performing immunohistochemical staining. The primary antibodies used for immunohistochemical staining were mouse monoclonal antibody to human p34(cdc2), p27(Kip1), p21(WAF1/Cip1), p53, ER and PR.
RESULTS
The expression rates of p34(cdc2), p21(WAF1/Cip1) and p53 were 29.3%, 40.2% and 49.1% in breast carcinomas, respectively. In normal breast tissues, p34(cdc2), p21(WAF1/Cip1) and p53 were not expressed. The p34(cdc2) was expressed in the cytoplasm of cancer cells. The expression rate of p27(Kip1) was 29.3% in breast carcinomas and 100% in normal breast tissues, so the loss of p27(Kip1) expression in breast cancer was noted. The high expression of p21(WAF1/Cip1) in neoplastic cells was associated with the p53 expression (p=0.03). The expression of p27(Kip1) was correlated with that of the progesterone receptor (PR) (p=0.04) and the expression of p21(WAF1/Cip1) was correlated with that of positivity for estrogen receptor (ER) (p=0.04) and PR (p=0.04). No correlation was demonstrated between the mean patient survival and the expression rate of p34(cdc2), p27(Kip1), p21(WAF1/Cip1) and p53.
CONCLUSIONS
The loss of the normal cell growth cycle by the abnormal expression of cyclin dependent kinases and their inhibitors and the steroid hormones may play an important role in human breast carcinogenesis. The p53 dependent p21(WAF1/Cip1) pathway, the p27(Kip1) protein loss and the cdc2 overexpression were important in development and progression of human breast cancer.

Expressions of E2F4 and E2F2 Transcription Factors in Breast Carcinoma.: Eun Young Kim, Hyun Jin Jo, Mi Ja Lee; Korean J Pathol. 2005;39(5):301-306.

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Abstract PDF: BACKGROUND
The E2F family (E2F1 to E2F6) of transcription factors plays a key role in cell cycle progression. Some act as oncogenes and others act as tumor suppressor genes (TSG) in a tissue-specific manner. E2F4 may function as a TSG. However, the role of E2F4 in breast carcinogenesis remains controversial. Also the clinical impact of E2F2 expression on breast cancer remains unknown.
METHODS
Expressions of E2F4 and E2F2 were assessed immunohistochemically in 113 breast carcinomas and were compared with clinicopathological variables, expressions of G1/S checkpoint proteins (p16, cyclin D1 and Rb), and DNA ploidy to identify their possible role and to assess their prognostic value in breast cancer.
RESULTS
Expressions of E2F4 and E2F2 were detected in 48 cases (42.5%) and 66 cases (58.4%), respectively. Expressions of E2F4 and E2F2 were significantly correlated with large tumor size (p<0.001) and lymph node metastasis (p<0.001). There was no correlation between expressions of E2F4 or E2F2 and any other variables, including age, histologic grade, DNA ploidy and expressions of p16, cyclin D1 and Rb.
CONCLUSIONS
These results suggest that expressions of E2F4 and E2F2 are associated with growth and spread of breast cancer and indicate poor prognosis.

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