Various new prognostic indicators have been identified for mammary carcinomas, but the issue of their significance remains unsettled. The prognostic impact of p53, c-erbB-2, and topoisomerase II alpha expression was investigated in relation to standard prognostic factors for carcinomas of the breast and to the tumour cell growth fraction. Paraffin-embedded specimens of 356 node-negative infiltrating ductal carcinomas were stained immunohistochemically using a polyclonal antiserum to c-erbB-2, and the monoclonal antibodies DO-1 (p53), Ki-S4 (topoisomerase II alpha), and Ki-S5 (Ki-67). The patients were followed for a median duration of 99 months. Both p53 and c-erbB-2 were significantly associated with high tumour grade, large tumour size, DNA aneuploidy, lack of steroid hormone receptors, young age, and increased topoisomerase II alpha and Ki-67 expression levels. The correlation of p53 and c-erbB-2 was not significant. Topoisomerase II alpha and Ki-67 scores closely paralleled each other, indicating that both reflect the proliferative activity of tumour cells. A univariate analysis of overall (OS), specific (SS), and disease-free survival (DFS) revealed all the above-mentioned parameters to be statistically significant except patient age, which was relevant only to overall survival. Multivariate analysis with inclusion of all covariates selected tumour size and proliferation (topoisomerase II alpha and Ki-67) indices as independent predictors of survival in all three models. No additional information was gained by p53 or c-erbB-2. It is concluded that the proliferative activity, as assessed by topoisomerase II alpha or Ki-67 immunostaining, is the most useful indicator of breast cancer prognosis, except for tumour size.

Correlation between p53, c-erbB-2, and topoisomerase II alpha expression, DNA ploidy, hormonal receptor status and proliferation in 356 node-negative breast carcinomas: prognostic implications.

Ion channels play a critical role in a wide variety of biological processes, including the development of human cancer. However, the overall impact of ion channels on tumorigenicity in breast cancer remains controversial. We conduct microarray meta-analysis on 280 ion channel genes. We identify candidate ion channels that are implicated in breast cancer based on gene expression profiling. We test the relationship between the expression of ion channel genes and p53 mutation status, ER status, and histological tumor grade in the discovery cohort. A molecular signature consisting of ion channel genes (IC30) is identified by Spearman’s rank correlation test conducted between tumor grade and gene expression. A risk scoring system is developed based on IC30. We test the prognostic power of IC30 in the discovery and seven validation cohorts by both Cox proportional hazard regression and log-rank test. 22, 24, and 30 ion channel genes are found to be differentially expressed with a change in p53 mutation status, ER status, and tumor histological grade in the discovery cohort. We assign the 30 tumor grade associated ion channel genes as the IC30 gene signature. We find that IC30 risk score predicts clinical outcome (P < 0.05) in the discovery cohort and 6 out of 7 validation cohorts. Multivariate and univariate tests conducted in two validation cohorts indicate that IC30 is a robust prognostic biomarker, which is independent of standard clinical and pathological prognostic factors including patient age, lymph node status, tumor size, tumor grade, estrogen and progesterone receptor status, and p53 mutation status. We identified a molecular gene signature IC30, which represents a promising diagnostic and prognostic biomarker in breast cancer. Our results indicate that information regarding the expression of ion channels in tumor pathology could provide new targets for therapy in human cancers.

/pdf/expression-profiling-of-ion-channel-genes-predicts-clinical-gz2weqb36k.pdf

Expression profiling of ion channel genes predicts clinical outcome in breast cancer

Epidermal growth factor receptor (EGFR) expression by human breast cancer has been shown to predict poor patient outcome, as has amplification of the c-erbB-2 proto-oncogene. We have developed a quantitative immunohistochemical method for measuring protein levels of both receptors and have applied this to a series of 123 breast primaries. We find EGFR expression is substantially lower than normal in nearly all breast cancers (97%). Quantification of p185erbB-2 indicates overexpression in 91% of the tumors. Two separate tumor populations are apparent with levels of c-erbB-2 expression ranging from 0.33 to 19 and 45 to 480 times normal, respectively. Within the lower population, p185erbB-2 expression is inversely related to EGFR expression (rank correlation, P < 0.0005). Using fluorescent in situ hybridization we show that tumors in the latter population have c-erbB-2 amplification and that amplification is restricted to this group. Our findings indicate that significant overexpression of p185erbB-2 occurs in the absence of amplification; these lower levels of expression may have functional significance. Fifty-three patients underwent in vivo bromodeoxyuridine labeling, allowing flow cytometric analysis of tumor cell cycle kinetics. EGFR expression correlates directly to the labeling index (P = 0.011) and indirectly to potential doubling time (P = 0.010), but not to the duration of the S-phase (P = 0.502). Conversely, p185erbB-2 expression does not relate to indices of proliferation. Our results have important implications for the use of both receptor types as therapeutic targets.

https://cancerres.aacrjournals.org/content/canres/56/16/3823.full.pdf

Quantitative Estimation of Epidermal Growth Factor Receptor and c-erbB-2 in Human Breast Cancer

Immunohistochemistry on cell blocks from fine-needle cytopunctures of primary breast carcinomas and lymph node metastases.

Breast cancer screening facilitates the early detection of breast cancer, although a significant number of tumors still arise in the interval between screening. The objective of this study was to measure the expression of five markers of proven prognostic significance in symptomatic breast cancer (estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2) in screen-detected and interval breast cancers to identify biological markers that may be associated with the emergence of symptomatic breast cancer in the screening interval. The expression of estrogen receptor, progesterone receptor, p53, Ki67, and c-erbB2 was assessed in a series of 51 true interval and 84 screened-detected invasive tumors by immunohistochemistry. Interval cancers tended to be of higher histological grade and were of larger pathological size than screen-detected cancers. Expression of estrogen receptor was 1.7-fold lower ( P P P P

https://clincancerres.aacrjournals.org/content/clincanres/5/10/2682.full.pdf

Differences in Ki67 and c-erbB2 Expression between Screen-detected and True Interval Breast Cancers

The mutation of the p53 gene is a common phenomenon in numerous human tumors, leading to the accumulation of nonfunctioning p53 protein in the cell nucleus, which can be detected by immunohistochemistry. In breast cancer, it has been suggested that the overexpression of p53 protein in the nucleus is an indicator of poor prognosis, which must be borne in mind in selecting coadjuvant treatment for each patient. This study is an immunohistochemical analysis of p53 expression in 153 cases of mammary carcinoma, correlating it with histological grade, axillary node status, hormone receptors, cell-proliferation fraction and expression of the c-erbB-2 oncoprotein. Of all the breast-cancer tissue analyzed, 43.79% was positive for p53. The overexpression of this protein bears a direct statistically significant relationship to histological grade, cell-proliferation fraction and c-erbB-2, and an inverse relationship to estrogen and progesterone receptors. No statistically significant relationship was found with axillary node status. The expression of p53 in poorly differentiated tumors-commonly receptor negative and with a high proliferation fraction-may indicate greater tumor aggressiveness and a high risk of relapse.

/pdf/p53-in-breast-cancer-its-relation-to-histological-grade-3qw7vftvfz.pdf

p53 in breast cancer. Its relation to histological grade, lymph-node status, hormone receptors, cell-proliferation fraction (ki-67) and c-erbB-2. Immunohistochemical study of 153 cases

In view of the limitations of conventional prognostic factors such as differentiation degree, metastatic lymph nodes, hormonal receptors and others, especially when early lesions are found, additional new markers have been studied, such as gene amplification and cell proliferation index, in order to choose the appropriate treatment. Primary breast carcinoma tumors from 97 patients were examined for differentiation degree, metastatic lymph nodes, hormonal receptors, c-erbB-2 amplification and cell proliferation index (Ki-67). A negative relationship with hormonal receptors and c-erbB-2 amplification, Ki-67 and differentiation degree was found, whereas the relationship between c-erbB-2, Ki-67 and differentiation degree was positive. No relationship was found between these factors and metastatic lymph nodes. The concurrence of high cell proliferation index, c-erbB-2 amplification and negative hormonal receptor presence would indicate a subpopulation with a high risk of recurrence. But a larger survival study is necessary to correlate these factors with clinical outcome.

Hormonal receptors, cell proliferation fraction (Ki-67) and c-erbB-2 amplification in breast cancer. Relationship between differentiation degree and axillary lymph node metastases.

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p53 in breast cancer. Its relation to histological grade, lymph-node status, hormone receptors, cell-proliferation fraction (ki-67) and c-erbB-2. Immunohistochemical study of 153 cases

Hormonal receptors, cell proliferation fraction (Ki-67) and c-erbB-2 amplification in breast cancer. Relationship between differentiation degree and axillary lymph node metastases.