Cell cycle deregulation in breast cancer subgroups and effects on proliferation, migration and tamoxifen resistance
Author
Summary, in English
Two of the key processes in malignant behaviour, proliferation and migration, have previously been reported to act as two opposing events in a cancer cell. We found that siRNA-mediated reduction of cyclin D1, a protein expressed in the active cell cycle, resulted in a migratory increase in cell lines negative of estrogen receptor (ER) expression. Conversely, in ER positive cell lines, downregulation of cyclin D1 resulted in decreased migratory capacity and a reduced number of stem-like cells, as measured by the mammosphere assay. Two agents inhibiting the cell cycle machinery, currently undergoing clinical trials, were further evaluated. Results showed that use of these agents in ER negative cell lines increased the number of stem-like cells, whereas a decrease was observed in the ER positive cells. These results point to the disparate effects of cell cycle-targeting treatments on breast cancer cells and highlight the importance of subgroup analysis.
The breast cancer therapy tamoxifen is widely used in patients with ER positive breast cancers; however resistance occurs in approximately one-third of patients. By analysing a breast cancer tumour material from a patient cohort randomised to receive tamoxifen or control treatment, we have found that a non-functional RB pathway in ER positive breast tumours was predictive of tamoxifen insensitivity. The non-functional RB pathway was however not correlated to prognosis, indicating that status of RB pathway holds purely treatment predictive information.
In addition, YAP1 was analysed in the tamoxifen randomised patient cohort and tumours lacking YAP1 protein expression were correlated with resistance to tamoxifen. Furthermore, in ER negative breast tumours, higher YAP1 expression was associated with increased proliferation whereas in ER positive tumours, YAP1 was negatively correlated to proliferation and grade. In vitro experiments downregulating YAP1 resulted in increased levels of ER and progesterone receptor (PgR), indicating deregulated signalling of the ER pathway.
Taken together, we have shown that the consequences of targeting cell cycle proteins may differ depending on ER expression. Furthermore, we have linked a non-functional pathway of the cell-cycle regulator RB and absent YAP1 protein expression to impaired tamoxifen response, identifying two potential biomarkers for predicting tamoxifen insensitivity.
Department/s
- Pathology, Malmö
- Molecular Pathology, Malmö
- BioCARE: Biomarkers in Cancer Medicine improving Health Care, Education and Innovation
Publishing year
2013
Language
English
Publication/Series
Lund University Faculty of Medicine Doctoral Dissertation Series
Volume
2013:13
Full text
Document type
Dissertation
Publisher
Department of Laboratory Medicine, Lund University
Topic
- Clinical Medicine
Keywords
- Breast cancer
- subgroups
- proliferation
- migration
- stem cells
- tamoxifen
- estrogen receptor
Status
Published
Research group
- Pathology, Malmö
- Molecular Pathology, Malmö
- Göran Landberg´s Group
Supervisor
- Göran Landberg
- Håkan Axelson
ISBN/ISSN/Other
- ISSN: 1652-8220
- ISBN: 978-91-87189-82-1
Defence date
22 February 2013
Defence time
09:15
Defence place
Jan Waldenströms gata 59, SUS Malmö, Main lecture hall
Opponent
- Young Leonie (Associate professor)