Quantitative Immuno cytochemical Assays of P-glycoprotein in Breast Carcinomas: Correlation to Messenger RNA Expression and to Immunohistochemical Prognostic Indicators

Charpin, Colette; Vielh, P.; Duffaud, F.; Devictor, B; Andrac, L; Lavaut, Marie‐Noëlle; Allasia, Claude; Horschowski, N; Piana, L

doi:10.1093/jnci/86.20.1539

Cited by 78 publications

(60 citation statements)

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“…Interestingly, membranous and cytoplasmic P-gp staining was often seen concomitantly with nuclear p53 staining in the same tumour cells. Correlation of expression between p53 and P-gp positivity has recently also been described in a group of 231 operable breast carcinomas, where 78% of P-gp-positive samples were also positive for p53 (Charpin et al, 1994).…”

Section: Discussionmentioning

confidence: 65%

p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer

Linn

Honkoop²,

Hoekman³

et al. 1996

Br J Cancer

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Summary Expression of both P-glycoprotein (P-gp) and mutant p53 have recently been reported to be associated with poor prognosis of breast cancer. The expression of P-gp is associated in vitro and in vivo with cross-resistance to several anti-cancer drugs. p53 plays a regulatory role in apoptosis, and mutant p53 has been suggested to be involved in drug resistance. Interestingly, in vitro experiments have shown that mutant p53 can activate the promoter of the MDRI gene, which encodes P-gp. We investigated whether p53 and P-gp are simultaneously expressed in primary breast cancer cells and analysed the impact of the co-expression on patients' prognosis. Immunohistochemistry was used to investigate P-gp expression (JSB-1, C219) and nuclear p53 accumulation (DO-7) in 20 operable chemotherapy untreated and 30 locally advanced breast cancers undergoing neoadjuvant chemotherapy with doxorubicin and cyclophosphamide. Double immunostaining showed that P-gp expression and nuclear p53 accumulation often occur concomitantly in the same tumour cells. A correlation between p53 and P-gp expression was found in all 50 breast cancers (P=0.003; Fisher's exact test). P-gp expression, nuclear p53 accumulation, and co-expression of p53 and P-gp were more frequently observed in locally advanced breast cancers than in operable breast cancers (P=0.0004; P=0.048; P=0.002 respectively, Fisher's exact test). Co-expression of p53 and P-gp was the strongest prognostic factor for shorter survival by multivariate analysis (P=0.004) in the group of locally advanced breast cancers (univariate analysis: P=0.0007). Only 3 out of 13 samples sequentially taken before and after chemotherapy displayed a change in P-gp or p53 staining. In conclusion, nuclear p53 accumulation is often associated with Pgp expression in primary breast cancer, and simultaneous expression of p53 and P-gp is associated with shorter survival in locally advanced breast cancer patients. Co-expression of P-gp and mutant p53 belong to a series of molecular events resulting in a more aggressive phenotype, drug resistance and poor prognosis.

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Section: Discussionmentioning

confidence: 65%

p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer

Linn

Honkoop²,

Hoekman³

et al. 1996

Br J Cancer

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“…The appropriate threshold of prognostic significance for a given marker was determined as previously recommended 33 and described. 22,[24][25][26][27][28][29][30][31] Logistic regression (with ROC curves) was then used to identify the combination of markers with the best sensitivity and specificity indicative of a proteomic signature of poor prognosis.…”

Section: Discussionmentioning

confidence: 99%

“…From the images acquired with 203 magnification, a new set of images was next computed, one for each core. For color analysis of the core images, the SAMBA ''immuno'' software was applied as previously reported [24][25][26][27][28][29][30][31] in usual full tissue sections.…”

Section: Image Analysismentioning

confidence: 99%

“…In particular, quantification of immunoprecipitates with automated computer-assisted devices relying on densitometry allows more objective analysis of results. [24][25][26][27][28][29][30][31] Also, quantitative data are more appropriate for statistical analysis and permit more valid studies, although some variation in interpretation of results can still occur. 32 Our objective in the present study was to determine immunohistochemical criteria for phenotyping of tumors of poor prognosis, and particularly for metastatic risk that would be economically applicable for individual patients with breast carcinoma, using the latest methodology for standardization and quality control.…”

mentioning

confidence: 99%

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A signature predictive of disease outcome in breast carcinomas, identified by quantitative immunocytochemical assays

Charpin

Secq

Giusiano

et al. 2009

Intl Journal of Cancer

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Quantitative immunocytochemical assays of 1,200 breast carcinomas were assessed after construction of tissue microarrays. A total of 42 markers were evaluated for prognostic significance by univariate log rank test (mean follow‐up, 79 months), using quantitative scoring by an image analysis device and specific software. Complete data were obtained for 924 patients, for whom 27 of the 42 markers proved to be significant prognostic indicators. Analysis of these 27 markers by logistic regression showed that 18 (cMet, CD44v6, FAK, moesin, caveolin, c‐Kit, CK14, CD10, P21, P27, pMAPK, pSTAT3, STAT1, SHARP2, FYN, ER, PgR and c‐erb B2), and 15 when ER, PgR and c‐erb B2 were excluded, were 80.52% and 78.9% predictive of disease outcome, respectively. The immunocytochemical assays on 4 micron thick sections of fixed tissue are easy to handle in current practice and are cost‐effective. Quantitative densitometric measurement of immunoprecipitates by computer‐assisted devices from digitized microscopic images allows standardized high‐throughput “in situ” molecular profiling within tumors. It is concluded that this 15 marker immunohistochemical signature is suitable for current practice, since performed on paraffin sections of fixed tumor samples, and can be used to select patients needing more aggressive therapy, since this signature is about 80% predictive of poor clinical outcome. Also, the markers included in the signature may be indicative of tumor responsiveness to current chemotherapy or suggest new targets for specific therapies. © 2008 Wiley‐Liss, Inc.

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“…The two parameters of the densitometric analysis, the percentages of positive immunostained surfaces (membrane and cytoplasm) vs counterstained surface and mean optical density (MOD), which depends upon the staining intensity (SAMBA arbitrary units scale: 0-255), were obtained as reported previously (Charpin et al, 1988(Charpin et al, , 1992(Charpin et al, , 1993(Charpin et al, , 1994(Charpin et al, , 1995a.…”

Section: Image Analysismentioning

confidence: 99%

c-erbB-2 oncoprotein detected by automated quantitative immunocytochemistry in breast carcinomas correlates with patients' overall and disease-free survival

Charpin

García²,

Bouvier³

et al. 1997

Br J Cancer

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Summary The prognostic significance of c-erbB-2 oncoprotein overexpression detected in tumours by immunocytochemical assays (ICAs) was investigated in 148 breast carcinomas. ICAs were performed under optimal technical conditions with frozen tissue sections and included automated immunoperoxidase technique and computer-assisted analysis (densitometry) of digitized coloured microscopic images. Results of quantitative ICAs (expressed in percentages of c-erbB-2-positive surfaces and mean optical densities) were correlated with the patients' follow-up in axillary lymph node-positive (N+) and node-negative (N-) subgroups of patients. Patients' follow-up ranged from 9 months (for the first death) to 101 months (for the 121 alive patients) with a 62.5 months mean overall follow-up. It was shown that marked c-erbB-2 immunocytochemical expression in tumours (cut-off point 35%) significantly correlated with the patients' poor overall survival in N+ and in N patients (Kaplan-Meier, log-rank test, P = 0.045 and P = 0.015). Also, marked c-erbB-2 immunohistochemical expression correlates with short disease-free (P = 0.005), recurrence-free (P = 0.048) and metastasis-free survival (P = 0.05) (Kaplan-Meier, log-rank test) in N+, but not in N-subgroups. It is concluded that in optimal conditions (automated and quantitative ICAs on frozen sections) c-erbB immunohistochemical expression is a significant prognostic indicator in terms of overall and disease-free survival. The c-erbB-2 protein prognostic significance is independent of node status in terms of overall survival, but not of disease-free survival.

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Quantitative Immuno cytochemical Assays of P-glycoprotein in Breast Carcinomas: Correlation to Messenger RNA Expression and to Immunohistochemical Prognostic Indicators

Cited by 78 publications

References 0 publications

p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer

p53 and P-glycoprotein are often co-expressed and are associated with poor prognosis in breast cancer

A signature predictive of disease outcome in breast carcinomas, identified by quantitative immunocytochemical assays

c-erbB-2 oncoprotein detected by automated quantitative immunocytochemistry in breast carcinomas correlates with patients' overall and disease-free survival

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