| 1. |
- Berglund, Pontus
(author)
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Cell cycle perspectives on breast cancer cell behaviour
- 2008
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Doctoral thesis (other academic/artistic)abstract
- Uncontrolled proliferation and the capacity to infiltrate surrounding tissues are two important characteristics of aggressive tumour cells. Previous observations in both colorectal cancer and basal cell carcinoma indicated that infiltrative tumour cell behaviour might be counteracted by a high proliferative activity, suggesting a coordination of these two activities at the cellular level. Here we studied the potential relation between proliferative activity and migratory behaviour in breast cancer, by focusing on the cell cycle regulatory proteins cyclin E and cyclin D1. By expressing cyclin E in a breast cancer cell line we obtained experimental results indicating that increased proliferative activity obstructed migratory and invasive capacity. When validating these results in a large set of primary breast cancers, we observed that increasing cyclin E levels correlated with a less infiltrative tumour growth appearance – a finding in line with our experimental results. Several studies have proposed that cyclin E is strongly associated with poorer disease outcome in breast cancer. Therefore, we continued to investigate the potential prognostic relevance of the inverse relation between cyclin E and infiltrative tumour growth. We revealed a distinct subgroup of less infiltrative, cyclin E high breast cancers with a relatively favourable prognosis. This subgroup was an important exception compared to the majority of tumours where cyclin E indeed correlated to a poorer outcome. We also tried to delineate in detail how the migratory capacities of tumour cells related to cell cycle activities. Synchronised G0/early G1 cells displayed an increased migratory potential compared to both late G1/S-phase cells as well as unsynchronised, actively cycling cells. Further, silencing of cyclin D1 in two cell lines indicated a novel CDK- and cell cycle independent function of cyclin D1 in restraining migratory capacity. This novel role of cyclin D1 seemed to influence the behaviour of ER positive breast tumours, where cyclin D1 high tumours were in general of smaller size and, further, exhibited a somewhat less infiltrative growth pattern. In addition, increased cyclin D1 levels correlated to a more favourable prognosis.
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| 2. |
- Berglund, Pontus, et al.
(author)
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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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In: Journal of Clinical Pathology. - : BMJ. - 0021-9746 .- 1472-4146. ; 61:2, s. 184-191
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Journal article (peer-reviewed)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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| 3. |
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| 4. |
- Berglund, Pontus, et al.
(author)
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Cyclin e overexpression reduces infiltrative growth in breast cancer - Yet another link between proliferation control and tumor invasion
- 2006
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In: Cell Cycle. - 1551-4005. ; 5:6, s. 606-609
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Journal article (peer-reviewed)abstract
- Overexpression of cyclin E is strongly linked to an aggressive phenotype and poor prognosis in breast cancer. Unexpectedly, it has been shown that cyclin E overexpression decreases mobility and invasiveness of breast cancer cells. In fact, in a study of 985 breast cancers, cyclin E correlated with less infiltrative growth. This suggests a novel function for cyclin E in breast cancer tumorigenesis and a mutual control of proliferation and invasive behavior.
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| 5. |
- Dunér, Pontus, et al.
(author)
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Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease.
- 2009
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In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; Feb 14., s. 593-603
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Journal article (peer-reviewed)abstract
- Abstract. Dunér P, To F, Alm R, Gonçalves I, Fredrikson GN, Hedblad B, Berglund G, Nilsson J, Bengtsson E (Malmö University Hospital, Lund University, Lund, Sweden). Immune responses against fibronectin modified by lipoprotein oxidation and their association with cardiovascular disease. J Intern Med 2009; doi: 10.1111/j.1365-2796.2008.02067.xObjectives. Accumulation and subsequent oxidation of LDL in the arterial wall are considered as key events in the development of atherosclerosis. We have investigated the possibility that LDL oxidation results in release of aldehydes that modify surrounding matrix proteins and that this may target immune responses against the plaque extracellular matrix and modulate the disease progression. Results. Using custom-made ELISAs we demonstrate that human plasma contains autoantibodies against aldehyde-modified fibronectin (FN) and to a lesser extent also other extracellular matrix proteins including collagen type I, type III, and tenascin-C. Immunohistochemistry and western blot analysis showed that aldehyde-modified FN is present in human atherosclerotic plaques and that aldehydes generated by oxidation of LDL formed adducts with FN in vitro. We also demonstrate that aldehyde-modification of FN results in a loss of its ability to promote basal secretion of cytokines and growth factors from cultured macrophages without affecting the ability of the cells to respond to stimulation with LPS. A prospective clinical study demonstrated that subjects that subsequently developed acute myocardial infarction or sudden cardiac death had lower baseline levels of autoantibodies against aldehyde-modified FN than matched controls. Conclusions. These observations demonstrate that oxidation of LDL in the arterial wall may lead to aldehyde-modification of surrounding extracellular matrix proteins and that these modifications may affect macrophage function and activate autoimmune responses of pathophysiological importance for the development of atherosclerosis.
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