Retinoblastoma Protein in Human Breast Carcinoma: Immunohistochemical Study Using a New Monoclonal Antibody Effective on Routinely Processed Tissues

Anderson, James; Tiniakos, Dina; McIntosh, Gary; Autzen, Pernille; Henry, James A.; Thomas, Myles D.; Reed, Jennifer; Horne, Glenda M.; Lennard, T. W. J.; Angus, Brian; Horne, C. H. W.

doi:10.1002/(sici)1096-9896(199609)180:1<65::aid-path607>3.0.co;2-c

Cited by 23 publications

(10 citation statements)

References 32 publications

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“…A similar effect has been reported for introduction of antisense p21 or p27 (Carroll et al, 2000;Cariou et al, 2000), and of a SV40 large T mutant that results in inactivation of pRb, leading to sustained E2F activity (Varma and Conrad, 2000). Translating these findings to the clinical situation, it is remarkable that overexpression of cylin A and absence of Rb expression in the primary breast cancer have been associated with failure to tamoxifen treatment in large series of breast cancer cases (Michalides et al, 2002;Anderson et al, 1996). In the former study cyclin D1 overexpression, however, was not found to be associated with tamoxifen resistance.…”

Section: Discussionsupporting

confidence: 53%

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

et al. 2002

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Estrogen receptor-mediated transcription is enhanced by overexpression of G1/S cyclins D1, E or A in the presence as well in the absence of estradiol. Excess of G1/S cyclins also prevents the inhibition of transactivation of estrogen receptor (ER) by the pure antiestrogen ICI 182780. Cyclin D1 mediates this transactivation independent of complex formation to its CDK4/6 partner. This raises the possibility that overexpression of G1/S cyclins renders growth of ER-positive breast cancer hormone-independent and resistant to treatment with antiestrogens. Transient transfection of ER-positive breast cancer cell lines T47D and MCF7 with G1/S cyclins could overcome the growth arrest induced by ICI 182780 treatment. The ability of various cyclin D1 mutants to overcome the ICI 182780 mediated growth arrest corresponded with their ability to stimulate cyclin A-and E2F-promoter based reporter activities in the presence of ICI 182780. Transfection of a mutant cyclin D1 (cyclin D1-KE) that was unable to bind CDK4 and was reported to transactivate ER in the presence of ICI 182780, could not stimulate proliferation in ICI 182780 treated cells. On the other hand, cyclin D1-LALA, which is unable to stimulate ERE transactivation, could overcome the ICI 182780 cell cycle arrest. Furthermore, transient transfection of T47D cells using cyclin D1 together with a catalytic inactive mutant of CDK4 (CDK4-DN) indicated that the observed effect is due to binding to CDK inhibitors. However, a moderate, sixfold overexpression of cyclin D1 in stably transfected MCF7 cells did not overcome the ICI 182780 mediated growth arrest. These results indicate that CDK-independent transactivation of the estrogen receptor by cyclin D1 is by itself, not sufficient to result in estradiol-independent growth of breast cancer cells, whereas a vast overexpression of G1/S cyclins is able to do so, most likely by capturing of CDK inhibitors.

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Section: Discussionsupporting

confidence: 53%

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

et al. 2002

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“…Although 20 ± 25% of breast cancer cell lines examined lack functional pRb, all estrogen-responsive breast cancer cell lines identi®ed to date contain wild type pRb T'Ang et al, 1988). In addition, in one study of primary breast cancers a signi®cant correlation was observed between the absence of pRb expression and a failure to respond to antiestrogen therapy (Anderson et al, 1996). Together, these data suggest that hormone dependence cannot be maintained in the absence of pRb function, and that changes in pRb status or regulation could be involved in the progression of tumors to antiestrogen resistance.…”

Section: Discussionmentioning

confidence: 99%

Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain

Varma

Conrad

2000

Oncogene

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“…[11][12][13][14] Rb immunohistochemistry studies have provided conflicting results concerning prognosis and response to therapies, and also because of the use of different immunohistochemistry cutoff. 10,[14][15][16][17][18][19][20] The results reported by Derenzini et al 16 indicated that only the absence but not hyperphosphorylation of Rb protein predicts clinical outcome. However, it should be noted that immunohistochemistry expression of Rb has provided contradictory interpretations concerning correlation with RB1 gene status.…”

Section: Discussionmentioning

confidence: 96%

“…[11][12][13][14] Unfortunately, immunohistochemistry studies showing a decrease in or lack of Rb protein expression have provided conflicting results concerning prognosis and response to therapies. 10,[14][15][16][17][18][19][20] Rb is inactivated by cyclin-dependent kinase (CDK)4-mediated phosphorylation, and the kinase activity of CDK4 is suppressed by p16INK4a (p16). Because inactivation of Rb results in the upregulation of p16 expression, high levels of p16 were used as an immunohistochemistry surrogate of Rb loss, mainly in squamous cell carcinomas harboring high-risk papilloma virus.…”

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confidence: 99%

P16 but not retinoblastoma expression is related to clinical outcome in no-special-type triple-negative breast carcinomas

et al. 2014

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Triple-negative breast carcinomas represent a tumor group of pivotal clinical importance given the lack of target therapies. The prognostic significance of triple-negative breast carcinomas remains unclear because of their histological and molecular heterogeneity. Currently, neither prognostic nor predictive factors are available for these tumors. Retinoblastoma (Rb) pathway loss has been linked to clinical outcome in various cancer types, including breast cancer. We investigated the association between Rb and p16 protein expression and clinical outcome in no-special-type triple-negative breast carcinomas. Immunohistochemical staining for Rb, p16, p53 and CK5 was carried out on a section from archival specimens of 117 no-special-type triple-negative breast carcinomas. Immunopositive p16 (p16 þ ) and immunonegative Rb (Rb À ) staining were seen in 49.5% and in 24.8% of tumors, respectively. There was an inverse correlation between p16 þ and Rb À (Po0.001). P16 þ was correlated with G3 grade (Po0.001), high Ki-67 (P ¼ 0.03), p53 overexpression (Po0.001) and CK5 immunopositivity (P ¼ 0.01). Rb À was not associated with any clinicopathologic variable. Follow-up and therapy data were available in 95 patients. In 20 patients treated with surgery only, neither p16 þ nor Rb À immunostaining were associated with disease-free survival and overall survival. In 75 patients treated with adjuvant chemotherapy, p16 þ was associated with good response to therapy with significant increased disease-free survival (P ¼ 0.001) and showed a trend towards a statistical significance for increased overall survival (P ¼ 0.056); Rb À were not associated with disease-free survival and overall survival. In multivariate analysis, p16 þ was independently associated with disease-free and overall survival, with a hazard ratio of 0.18 (95% CI: 0.06-0.51; P ¼ 0.001) and 0.21 (95% CI: 0.06-0.74; P ¼ 0.015), respectively. In patients with no-specialtype triple-negative breast carcinomas, p16 þ is related to good response to adjuvant chemotherapy and can be considered the best surrogate marker for Rb pathway loss.

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Retinoblastoma Protein in Human Breast Carcinoma: Immunohistochemical Study Using a New Monoclonal Antibody Effective on Routinely Processed Tissues

Cited by 23 publications

References 32 publications

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

Involvement of G1/S cyclins in estrogen-independent proliferation of estrogen receptor-positive breast cancer cells

Reversal of an antiestrogen-mediated cell cycle arrest of MCF-7 cells by viral tumor antigens requires the retinoblastoma protein-binding domain

P16 but not retinoblastoma expression is related to clinical outcome in no-special-type triple-negative breast carcinomas

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