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Cyclin D1, Id1 and EMT in breast cancer

Tobin, Nicholas P. ; Sims, Andrew H. ; Lundgren, Katja L. ; Lehn, Sophie LU and Landberg, Göran LU (2011) In BMC Cancer 11.
Abstract
Background: Cyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1... (More)
Background: Cyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1 and EMT, as well as clinical properties in primary breast cancer. Methods: Protein and gene expression of ID1, CCND1 and EMT markers were determined in MDA-MB-231 and ZR75 cells by western blot and qPCR. Cell migration and promoter occupancy were monitored by transwell and ChIP assays, respectively. Gene expression was analysed from publicly available datasets. Results: The increase in cell migration following cyclin D1 silencing in MDA-MB-231 cells was abolished by Id1 siRNA treatment and we observed cyclin D1 occupancy of the Id1 promoter region. Moreover, ID1 and SNAI2 gene expression was increased following cyclin D1 knock-down, an effect reversed with Id1 siRNA treatment. Similar migratory and SNAI2 increases were noted for the ER-positive ZR75-1 cell line, but in an Id1-independent manner. In a meta-analysis of 1107 breast cancer samples, CCND1(low)/ID1(high) tumours displayed increased expression of EMT markers and were associated with reduced recurrence free survival. Finally, a greater percentage of CCND1(low)/ID1(high) tumours were found in the EMT-like 'claudin-low' subtype of breast cancer than in other subtypes. Conclusions: These results indicate that increased migration of MDA-MB-231 cells following cyclin D1 silencing can be mediated by Id1 and is linked to an increase in EMT markers. Moreover, we have confirmed a relationship between cyclin D1, Id1 and EMT in primary breast cancer, supporting our in vitro findings that low cyclin D1 expression can be linked to aggressive features in subgroups of breast cancer. (Less)
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organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Cyclin D1, Id1, EMT, breast cancer, migration, recurrence-free, survival, claudin-low
in
BMC Cancer
volume
11
publisher
BioMed Central (BMC)
external identifiers
  • wos:000295850200001
  • scopus:80053358875
  • pmid:21955753
ISSN
1471-2407
DOI
10.1186/1471-2407-11-417
language
English
LU publication?
yes
id
d2eb2476-92ab-4e44-b8b1-aa9ff2ae9af0 (old id 2212935)
date added to LUP
2016-04-01 14:55:29
date last changed
2022-02-19 21:31:18
@article{d2eb2476-92ab-4e44-b8b1-aa9ff2ae9af0,
  abstract     = {{Background: Cyclin D1 is a well-characterised cell cycle regulator with established oncogenic capabilities. Despite these properties, studies report contrasting links to tumour aggressiveness. It has previously been shown that silencing cyclin D1 increases the migratory capacity of MDA-MB-231 breast cancer cells with concomitant increase in 'inhibitor of differentiation 1' (ID1) gene expression. Id1 is known to be associated with more invasive features of cancer and with the epithelial-mesenchymal transition (EMT). Here, we sought to determine if the increase in cell motility following cyclin D1 silencing was mediated by Id1 and enhanced EMT-features. To further substantiate these findings we aimed to delineate the link between CCND1, ID1 and EMT, as well as clinical properties in primary breast cancer. Methods: Protein and gene expression of ID1, CCND1 and EMT markers were determined in MDA-MB-231 and ZR75 cells by western blot and qPCR. Cell migration and promoter occupancy were monitored by transwell and ChIP assays, respectively. Gene expression was analysed from publicly available datasets. Results: The increase in cell migration following cyclin D1 silencing in MDA-MB-231 cells was abolished by Id1 siRNA treatment and we observed cyclin D1 occupancy of the Id1 promoter region. Moreover, ID1 and SNAI2 gene expression was increased following cyclin D1 knock-down, an effect reversed with Id1 siRNA treatment. Similar migratory and SNAI2 increases were noted for the ER-positive ZR75-1 cell line, but in an Id1-independent manner. In a meta-analysis of 1107 breast cancer samples, CCND1(low)/ID1(high) tumours displayed increased expression of EMT markers and were associated with reduced recurrence free survival. Finally, a greater percentage of CCND1(low)/ID1(high) tumours were found in the EMT-like 'claudin-low' subtype of breast cancer than in other subtypes. Conclusions: These results indicate that increased migration of MDA-MB-231 cells following cyclin D1 silencing can be mediated by Id1 and is linked to an increase in EMT markers. Moreover, we have confirmed a relationship between cyclin D1, Id1 and EMT in primary breast cancer, supporting our in vitro findings that low cyclin D1 expression can be linked to aggressive features in subgroups of breast cancer.}},
  author       = {{Tobin, Nicholas P. and Sims, Andrew H. and Lundgren, Katja L. and Lehn, Sophie and Landberg, Göran}},
  issn         = {{1471-2407}},
  keywords     = {{Cyclin D1; Id1; EMT; breast cancer; migration; recurrence-free; survival; claudin-low}},
  language     = {{eng}},
  publisher    = {{BioMed Central (BMC)}},
  series       = {{BMC Cancer}},
  title        = {{Cyclin D1, Id1 and EMT in breast cancer}},
  url          = {{https://lup.lub.lu.se/search/files/4247300/2342596.pdf}},
  doi          = {{10.1186/1471-2407-11-417}},
  volume       = {{11}},
  year         = {{2011}},
}