Rakha, E. A. et al. Expression of BRCA1 protein in breast cancer and its prognostic significance. Hum. Pathol. 39, 857-865

Department of Histopathology, The Breast Unit, Nottingham City Hospital, University of Nottingham, NG5 1PB Nottingham, UK.
Human pathology (Impact Factor: 2.77). 07/2008; 39(6):857-65. DOI: 10.1016/j.humpath.2007.10.011
Source: PubMed


BRCA1 is a tumor suppressor gene which, when mutated, is associated with the development of hereditary breast cancers. In sporadic tumors, although inherent gene mutations are rare, loss of BRCA1, resulting from reduced expression or incorrect subcellular localization, is postulated to be important. The purpose of the current study was to examine the expression and localization of BRCA1 protein and to assess its prognostic value, in a well-characterized series of unselected breast carcinomas. We have examined BRCA1 in a series of invasive breast carcinoma (1940 cases) using tissue microarray and immunohistochemistry, to evaluate its expression pattern and to correlate this with clinicopathologic variables and patient outcome. In breast cancer, complete loss of nuclear expression was observed in 223 cases (15%) and cytoplasmic expression was found in 541 breast cancers (36.6%). Absent or reduced nuclear BRCA1 expression was observed more frequently in ductal carcinoma of no special type and medullary-like carcinoma and less frequently in lobular and tubular mixed carcinomas. It was also associated with high-grade, advanced lymph node stage, larger size, vascular invasion, negative estrogen receptor, progesterone receptor and androgen receptor expression, and positive p53 and P-cadherin expression, and with the basal-like class of breast cancer. Altered BRCA1 was associated with shorter disease-free interval. Cytoplasmic expression was also associated with development of recurrence and positive EGFR and HER2 expression. It showed an inverse association with survival particularly in low-grade, small-size, and estrogen receptor-positive subgroups. In the grade 1 subgroup, multivariate analysis with adjustment for other prognostic factors showed that cytoplasmic expression of BRCA1 was an independent predictor of disease-free interval. BRCA1 alteration may play a significant role in the development and progression of breast cancer. Immunohistochemical assessment of BRCA1 expression could provide additional clinically relevant information in routine classification of breast cancer.

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Available from: Andrew R Green, Jul 27, 2015
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    • "It would be interesting to explore whether similar findings could be also observed with BECN1 protein expression. While transcriptional deregulation of BECN1 appears to play a significant role in breast cancer pathogenesis, other post-transcriptional regulatory mechanisms could be involved in BRCA1 deregulation, for example, aberrant subcellular localisation and deregulation in protein expression of BRCA1 (Rakha et al., 2008). The contribution of BRCA1 deregulation in the pathogenesis of breast cancer cannot be ruled out. "
    02/2015; 10(3). DOI:10.1016/j.ebiom.2015.02.012
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    • "In order to compare with the younger (<70 years) patients, patients with stage matched (cT1-2,N0-1,M0) TNBCs were retrieved from a previously characterised institutional database (Nottingham/Tenovus series) along with the data of the above mentioned biomarkers [14], [15], [16]. The Nottingham Tenovus series consists of clinical and biological data of younger (<70 years) patients with early operable primary breast cancer established in 1980s and tumours were prospectively analysed using IHC on TMAs, constructed using surgical specimens (N = 1809). "
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    ABSTRACT: Triple negative (ER, PgR and HER2 negative) breast cancers (TNBCs) are often considered as a poor prognostic phenotype. There is dearth of evidence showing the prevalence and biological behaviour of TNBCs in older women. This study aimed to analyse their biological characteristics in comparison with a well characterised younger series from a single centre with long term clinical follow-up. Over 37 years (1973-2010), 1,758 older (≥70 years) women with early operable (<5 cm) primary breast cancer were managed in a dedicated clinic and have complete clinical information available. Of these 813 patients underwent primary surgery and 575 had good quality tumour samples available for tissue microarray analysis using indirect immunohistochemistry. A total of 127 patients (22.1%) had TNBCs and full biological analysis of 15 biomarkers was performed. The results were compared with those of their younger (<70 years) counterparts 342 (18.9%) from a previously characterised, consecutive series of primary breast cancer treated in the same unit (1986-1998). The 127 older patients with TNBCs showed lower rates of Ki67 and CK 7/8 positivity and high rates of bcl2 and CK18 positivity when compared with their younger counterparts (p<0.05). There was no significant difference in the long term clinical outcome between the two age groups, despite the fact that 47% of the younger patients had adjuvant chemotherapy, while none in the older cohort received such treatment. EGFR, axillary stage and pathological size showed prognostic significance in older women with TNBCs on univariate analysis. Despite not having received adjuvant chemotherapy, the older series had clinical outcome similar to the younger patients almost half of whom had chemotherapy. This appears to be related to other biomarkers (in addition to ER/PgR/HER2) eg Ki67, bcl2 and cytokeratins which have different expression patterns influencing prognosis.
    PLoS ONE 07/2014; 9(7):e100573. DOI:10.1371/journal.pone.0100573 · 3.23 Impact Factor
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    • "BCP constitute a tumor subgroup associated with BRCA1 mutations. Tumors of patients with BRCA1 germline mutations usually display the basal core phenotype [52,53]. In this study we found that alphaB-crystallin is associated with BCP and BRCA1 mutational status but not with BRCA1 protein expression. "
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    ABSTRACT: BackgroundalphaB-crystallin is a small heat shock protein that has recently been characterized as an oncoprotein correlating with the basal core phenotype and with negative prognostic factors in breast carcinomas. The purpose of this study was to evaluate alphaB-crystallin with respect to clinicopathological parameters and the outcome of patients with operable high-risk breast cancer.MethodsA total of 940 tumors were examined, derived from an equal number of patients who had participated in two randomized clinical trials (paclitaxel-containing regimen in 793 cases). Immunohistochemistry for ER, PgR, HER2, Ki67, CK5, CK14, CK17, EGFR, alphaB-crystallin, BRCA1 and p53 was performed. BRCA1 mutation data were available in 89 cases.Resultsalphaβ-crystallin was expressed in 170 cases (18.1%) and more frequently in triple-negative breast carcinomas (TNBC) (45% vs. 14.5% non-TNBC, p < 0.001). alphaB-crystallin protein expression was significantly associated with high Ki67 (Pearson chi-square test, p < 0.001), p53 (p = 0.002) and basal cytokeratin protein expression (p < 0.001), BRCA1 mutations (p = 0.045) and negative ER (p < 0.001) and PgR (p < 0.001). Its overexpression, defined as >30% positive neoplastic cells, was associated with adverse overall survival (Wald’s p = 0.046). However, alphaB-crystallin was not an independent prognostic factor upon multivariate analysis. No interaction between taxane-based therapy and aβ-crystallin expression was observed.ConclusionsIn operable high-risk breast cancer, alphaB-crystallin protein expression is associated with poor prognostic features indicating aggressive tumor behavior, but it does not seem to have an independent impact on patient survival or to interfere with taxane-based therapy.Trial registrationsACTRN12611000506998 (HE10/97 trial) and ACTRN12609001036202 (HE10/00 trial).
    BMC Clinical Pathology 06/2014; 14(1):28. DOI:10.1186/1472-6890-14-28
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