Elevated expression of nuclear Hsp90 in invasive breast tumors

Diehl, Malissa; Idowu, Michael O.; Kimmelshue, Katherine N.; York, Timothy P.; Elmore, Lynne W.; Holt, Shawn E.

doi:10.4161/cbt.8.20.9639

Cited by 29 publications

(26 citation statements)

References 35 publications

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“…Allred score was based exclusively on cytoplasmic Hsp90 staining. Nevertheless, the significance of nuclear Hsp90 expression remains elusive, as some studies have not documented any nuclear Hsp90 expression in invasive ductal carcinomas [7], as opposed to other studies [24]. This finding has already been reported in invasive breast carcinomas and has been correlated with MHC class I expression [25].…”

Section: Discussionmentioning

confidence: 94%

Decreased Hsp90 expression in infiltrative lobular carcinoma: an immunohistochemical study

et al. 2010

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BackgroundElevated Hsp90 expression has been documented in breast ductal carcinomas, whereas decreased Hsp90 expression has been reported in precursor lobular lesions. This study aims to assess Hsp90 expression in infiltrative lobular carcinomas of the breast.MethodsTissue specimens were taken from 32 patients with infiltrative lobular carcinoma. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment: i) the percentage of positive cells and ii) the intensity were separately analyzed. Subsequently, the Allred score was adopted and calculated. The intensity was treated as an ordinal variable-score (0: negative, low: 1, moderate: 2, high: 3). Statistical analysis followed.ResultsAll infiltrative lobular carcinoma foci mainly presented with a positive cytoplasmic immunoreaction for Hsp90. Compared to the adjacent normal ducts and lobules, infiltrative lobular carcinoma exhibited a statistically significant decrease in Hsp90 expression, both in terms of Hsp90 positive cells (%) and Allred score (74.2 ± 11.2 vs. 59.1 ± 14.2 p = 0.0001; 7.00 ± 0.95 vs. 6.22 ± 1.01, p = 0.007, Wilcoxon matched-pairs signed-ranks test). Concerning the intensity of Hsp90 immunostaining only a marginal decrease was noted (2.16 ± 0.68 vs. 1.84 ± 0.63, p = 0.087, Wilcoxon matched-pairs signed-ranks test).ConclusionILC lesions seem to exhibit decreased Hsp90 expression, a finding contrary to what might have been expected, given that high Hsp90 expression is a trait of invasive ductal carcinomas.

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Section: Discussionmentioning

confidence: 94%

Decreased Hsp90 expression in infiltrative lobular carcinoma: an immunohistochemical study

et al. 2010

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“…It should be declared that nuclear staining was not taken into account at the calculation of Allred score, as the latter was based exclusively on cytoplasmic Hsp90 staining. At any case, the significance of nuclear Hsp90 expression remains elusive, as some studies have not documented any nuclear Hsp90 expression in invasive ductal carcinomas [9], whereas other researchers have [24]. Other researchers have correlated nuclear Hsp90 staining with MHC class I expression in invasive breast carcinomas [25].…”

Section: Discussionmentioning

confidence: 99%

Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions

et al. 2010

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BackgroundHsp90 (heat shock protein90) is a chaperone protein essential for preserving and regulating the function of various cellular proteins. Elevated Hsp90 expression seems to be a trait of breast cancer and may be an integral part of the coping mechanisms that cancer cells exhibit vis-à-vis stress. This manuscript tries to examine the immunohistochemical expression of Hsp90 all along the continuum of breast ductal lesions encompassing ductal hyperplasia without atypia (DHWithoutA), atypical ductal hyperplasia (ADH), ductal carcinoma in situ (DCIS) and invasive ductal carcinoma (IDC).MethodsTissue specimens were taken from 30 patients with DHWithoutA, 31 patients with ADH, 51 with DCIS and 51 with IDC. Immunohistochemical assessment of Hsp90 was performed both in the lesion and the adjacent normal breast ducts and lobules; the latter serving as control. Concerning Hsp90 assessment the percentage of positive cells and the intensity were separately analyzed. Subsequently, the Allred score was calculated. Post hoc analysis on the correlations between Hsp90 Allred score and possible predictors (grade, nodal status, tumor size, ER Allred score, PR Allred score, c-erbB-2 status and triple negative status) was conducted in IDC.ResultsHsp90 exhibited mainly cytoplasmic immunoreactivity. Hsp90 Allred score exhibited an increasing trend along the continuum of breast ductal lesions (Spearman's rho = 0.169, p = 0.031). Compared to the adjacent normal ducts and lobules, no statistically significant differences were noted in DHwithoutA, ADH and DCIS. Hsp90 expression (intensity, positive cells, Allred score) was higher in IDC, compared to the adjacent normal tissue. Higher Hsp90 expression was observed in grade 2/3 IDCs (borderline association) and tumors of larger size. At the univariable analysis, higher Hsp90 expression was associated with higher ER Allred score, PR Allred score and c-erbB-2 positivity in IDC. Triple-negative IDCs exhibited significantly lower Hsp90 expression. The multivariable logistic regression model revealed that between the three markers, solely ER Allred score and c-erbB-2 positivity were independently associated with higher Hsp90 expression in IDC.ConclusionThe above point to significant variability in Hsp90 expression with significant implications upon the effectiveness and limitations of anti-Hsp90 drugs.

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“…HSP90 function is thereby implicated in the establishment of each of the hallmarks of cancer (Neckers 2007) that were first proposed and recently extended by Hanahan and Weinberg (2011). In addition to its client proteins, HSP90 itself was overexpressed in a variety of tumors, e.g., skin (Becker et al 2004), prostate (Elmore et al 2008), breast (Diehl et al 2009), and colon (Milicevic et al 2008). The function of HSP90 in tumorigenesis led to considerable interest in the chaperone as a target in cancer therapy.…”

Section: Introductionmentioning

confidence: 99%

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

Jahns

Wilhelm

Greulich³

et al. 2011

Genes Nutr

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Due to protection of oncogenic proteins from degradation and enhancement of glycolytic phosphometabolites for synthetic processes, respectively, heat shock protein 90 (HSP90) and pyruvate kinase type M2 (PKM2) are important proteins for tumor growth. The present study was undertaken to investigate the susceptibility of both proteins and their encoding genes to the chemopreventive agent butyrate in human colon cells. Matched tissue of different transformation stages derived from 20 individual colon cancer patients was used for the experiments. The results of quantitative real-time PCR revealed a moderate increase of HSP90b and PKM2 mRNA in colon tumors (P \ 0.01) compared to normal tissues without relation to clinical parameters. The expression pattern could be confirmed for PKM2 protein by Western blot but not for HSP90b. During culturing with butyrate, the amount of PKM2 transcripts decreased in all three tissue types with the strongest effects observed in tumors (median fold decrease 45%, P \ 0.05). The protein data have not reflected this influence supposing a more gradual degradation rate due to a longer half-life of PKM2. In contrast,

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Elevated expression of nuclear Hsp90 in invasive breast tumors

Cited by 29 publications

References 35 publications

Decreased Hsp90 expression in infiltrative lobular carcinoma: an immunohistochemical study

Decreased Hsp90 expression in infiltrative lobular carcinoma: an immunohistochemical study

Hsp90 in the continuum of breast ductal carcinogenesis: Evaluation in precursors, preinvasive and ductal carcinoma lesions

Impact of butyrate on PKM2 and HSP90β expression in human colon tissues of different transformation stages: a comparison of gene and protein data

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