| 1. |
- Berglund, Pontus, et al.
(författare)
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Cyclin E confers a prognostic value in premenopausal breast cancer patients with tumours exhibiting an infiltrative growth pattern
- 2008
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Ingår i: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
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Tidskriftsartikel (refereegranskat)abstract
- Aims: To investigate the prognostic value of cyclin E in relation to tumour growth pattern by analysing stage II primary breast cancers from premenopausal women not subjected to any further adjuvant treatment. To analyse the value of cyclin E as a predictor of tamoxifen response, by comparing untreated and treated patients with oestrogen receptor positive tumours. Methods: Breast cancer samples, assembled in tissue microarrays, were immunohistochemically stained for cyclin E and evaluated regarding the presence of nuclear staining. The overall growth characteristics of each tumour were assessed using whole tissue sections. Results: Tumours displaying a pushing margin phenotype were strongly associated with high cyclin E levels, lymph node negative disease, a high histological grade and oestrogen receptor negativity, and exhibited a better prognosis compared to tumours with an infiltrative growth pattern. In the total cohort of non-treated patients (n = 187), cyclin E was not associated with recurrence free survival (RFS). However, when analysing the subgroup of tumours lacking a pushing growth pattern (n = 141), cyclin E was significantly associated with RFS, independent of histological grade and node status. There was no significant difference in tamoxifen response with regard to different cyclin E levels. Conclusion: The prognostic value of cyclin E in premenopausal breast cancer is limited to patients with breast carcinomas exhibiting an exclusively infiltrative growth pattern. This limitation could be explained by the presence of a small but distinct subgroup of cyclin E-high breast cancers with a pushing margin phenotype and a more favourable outcome.
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| 2. |
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| 3. |
- Loden, M, et al.
(författare)
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The cyclin D1 high and cyclin E high subgroups of breast cancer: separate pathways in tumorogenesis based on pattern of genetic aberrations and inactivation of the pRb node
- 2002
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Ingår i: Oncogene. - : Springer Science and Business Media LLC. - 1476-5594 .- 0950-9232. ; 21:30, s. 4680-4690
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Tidskriftsartikel (refereegranskat)abstract
- In an attempt to identify subtypes of breast cancer and pinpoint patterns of cell cycle regulatory defects associated with clinical behaviour, proliferation and other transformation associated events, a multitude of cell cycle regulatory proteins were analysed in a material of 113 primary breast cancers. Increased proliferation was observed in two different scenarios; (1) with high cyclin D1 and elevated retinoblastoma protein (pRb) phosphorylation, (cyclin D1(high) tumours) or (2) with high cyclin E protein but low cyclin D1 and lack of corresponding pRb phosphorylation (cyclin E high tumours) indicative of an interrupted pRb pathway. Characteristic for cyclin E-high tumours were further defects in p53, p27 and bcl-2, while c-erbB2 overexpression and c-myc amplification was found in both cyclin D1(high) and E-high tumours. Using transfected cell lines overexpressing cyclin E, cyclin E-high and D1(high) tumours were mimicked and the cyclin D1(high) cell line normalized the cyclin E kinase activity by an induction and redirection of p21 and p27 to the cyclin E complex whereas cyclin E-high cell lines obtained increased kinase activity with out redirection or inhibitors. Based on differences in genetic aberrations as well as function of the pRb node we therefore propose a model in which cyclin D1(high) and cyclin E-high tumours represent two alternative mechanisms to inactivate the pRb pathway and thereby achieve unrestrained growth in the tumorogenesis of breast cancer.
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| 4. |
- Stighall, Maria
(författare)
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Cyclin E overexpression and associated events in human breast cancer
- 2005
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Unrestrained proliferation is a hallmark of cancer and genetic defects within G1/S-phase regulation and the pRb pathway occur frequently. Proliferation control can be circumvented either by excess cyclin D1 or cyclin E, alterations that can define two alternative tumour biologic pathways in breast cancer. By overexpressing cyclin E in a cell line model system we demonstrate that the capacity of cells to normalize the level of active cyclin E/cdk2 was dependent on the ability to upregulate and re-direct p21 and p27 to the active kinase complex, as could be observed in ER positive and cyclin D1 high, but not the ER negative and cyclin E high cell lines. The results further indicated that cyclin E and associated kinase activities might regulate proliferation independent of pRb. One alternative substrate for cyclin E kinase is the ID2 protein. Upon ID2 overexpression, the proliferative capacity increased but the invasive potential of breast cancer cell lines decreased. In primary breast cancer, high ID2 expression was associated with a favourable outcome and a less aggressive and more differentiated luminal breast cancer phenotype. Next we evaluated the incidence of aberrant cyclin E expression in the S/G2/M-phases, and investigated the potential tumour biologic characteristics associated with impaired cyclin E degradation. Cyclin E overexpressing breast cancer cells lines displayed varying ability to degrade excess cyclin E, and exhibited prolonged S-phase progression. Tumours with aberrant cell cycle specific expression pattern of cyclin E correlated inversely with survival status of patients and there was a favour for c-myc amplification within this group of tumours. We further characterised potential novel functions of cyclin E, and breast cancer cell lines overexpressing cyclin E induced significant changes in gene expression related to cell adhesion. Cells further showed an impaired capacity to migrate and invade through ECM. In primary breast cancer we observed a positive correlation between cyclin E expression and tumours with a pushing growth pattern and a medullary breast cancer type, clearly validating the cell line observations. Due to the link between cyclin E and growth pattern, as well as survival, cyclin E expression was consequently associated with impaired prognosis exclusively in patients with breast cancer with an infiltrative growth pattern. Thus, the effects of cyclin E expression and breast cancer progression are multiple, including altered proliferation as well as tumour growth pattern.
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| 5. |
- Stighall, Maria, et al.
(författare)
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High ID2 protein expression correlates with a favourable prognosis in patients with primary breast cancer and reduces cellular invasiveness of breast cancer cells.
- 2005
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 115:3, s. 403-411
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Tidskriftsartikel (refereegranskat)abstract
- ID proteins have been implicated in the regulation of cell proliferation and differentiation in various cell types during normal development as well as in the formation of cancer. Our aim was to delineate the expression of ID2 by immunohistochemistry in primary breast cancer in order to detect potential associations with cell cycle regulatory proteins and/or clinicopathologic parameters. We further overexpressed ID2 in a breast cancer cell line to elaborate potential effects on proliferation and invasiveness. We observed large variations in ID2 expression in primary breast cancer, and the protein was localised to both the nucleus and cytoplasm. Interestingly, a high cytoplasmic ID2 protein level correlated with a favourable prognosis. Overexpressing ID2 in the MDA-MB-468 breast cancer cell line generated a marked cytoplasmic localisation of the protein and reduced the invasive capacity of cells. Modest enhancement of cell proliferation was further detected in ID2-overexpressing cells. In conclusion, ID2 protein expression varies substantially within primary breast tumours and high cytoplasmic levels of ID2 might reflect a less aggressive breast tumour phenotype.
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