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High-Resolution Genomic Analysis of the 11q13 Amplicon in Breast Cancers Identifies Synergy with 8p12 Amplification, Involving the mTOR Targets S6K2 and 4EBP1
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
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2011 (English)In: Genes, Chromosomes and Cancer, ISSN 1045-2257, E-ISSN 1098-2264, Vol. 50, no 10, 775-787 p.Article in journal (Refereed) Published
Abstract [en]

The chromosomal region 11q13 is amplified in 15-20% of breast cancers; an event not only associated with estrogen receptor (ER) expression but also implicated in resistance to endocrine therapy. Coamplifications of the 11q13 and 8p12 regions are common, suggesting synergy between the amplicons. The aim was to identify candidate oncogenes in the 11q13 region based on recurrent amplification patterns and correlations to mRNA expression levels. Furthermore, the 11q13/8p12 coamplification and its prognostic value, was evaluated at the DNA and the mRNA levels. Affymetrix 250K NspI arrays were used for whole-genome screening of DNA copy number changes in 29 breast tumors. To identify amplicon cores at 11q13 and 8p12, genomic identification of significant targets in cancer (GISTIC) was applied. The mRNA expression levels of candidate oncogenes in the amplicons [ RAD9A, RPS6KB2 (S6K2), CCND1, FGF19, FGF4, FGF3, PAK1, GAB2 (11q13); EIF4EBP1 (4EBP1), PPAPDC1B, and FGFR1 (8p12)] were evaluated using real-time PCR. Resulting data revealed three main amplification cores at 11q13. ER expression was associated with the central 11q13 amplification core, encompassing CCND1, whereas 8p12 amplification/gene expression correlated to S6K2 in a proximal 11q13 core. Amplification of 8p12 and high expression of 4EBP1 or FGFR1 was associated with a poor outcome in the group. In conclusion, single nucleotide polymorphism arrays have enabled mapping of the 11q13 amplicon in breast tumors with high resolution. A proximal 11q13 core including S6K2 was identified as involved in the coamplification/coexpression with 8p12, suggesting synergy between the mTOR targets S6K2 and 4EBP1 in breast cancer development and progression.

Place, publisher, year, edition, pages
Wiley-Blackwell , 2011. Vol. 50, no 10, 775-787 p.
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-70514DOI: 10.1002/gcc.20900ISI: 000294177300003OAI: diva2:440116

Funding Agencies|Swedish Cancer Foundation||Swedish Research Council||

Available from: 2011-09-12 Created: 2011-09-12 Last updated: 2014-02-10
In thesis
1. Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
Open this publication in new window or tab >>Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The prognosis of patients diagnosed with breast cancer has been considerably improved in the latest 25 years, as a result of continuous development of diagnostics and treatment regimens. Though, tumour diseases, for woman mainly lung cancer and breast cancer, still constitute of the most common causes of death in developed countries, following heart diseases. A future utopia is to develop more individualised therapy strategies, to further increase breast cancer survival, but also to decrease  the risk of severe side-effects of unnecessary treatments.

Normal mammary gland development is regulated by a complex interplay between growth factors and hormones, mainly oestrogen and progesterone, in different cell types. Breast cancer origin and progression is assumed to result from an imbalance in this interplay, leading to the so called “Hallmarks of cancer”, including unlimited cellular proliferation. A central hub in the regulation of proliferation is the intracellular mTOR signalling pathway. Antioestrogen therapy is widely used in breast cancer clinics, however resistance towards this treatment is a remaining problem, and overactivation of mTOR may be one reason behind. A new treatment regimen constituting a combination of mTOR inhibitors with endocrine therapy was recently clinically approved for advanced breast cancers. Although significant benefit for this combination treatment is evident for some patients, counteracting feedback mechanisms are assumed to diminish the effects.

The work presented in this thesis focuses on the genes S6K1, S6K2 and 4EBP1 which are main effectors of the intracellular mTOR signalling pathway and thereby secondary targets of the mTOR inhibitors. Our results suggests that the gene amplification status, expression levels of the corresponding mRNA and protein of S6K1, S6K2 and 4EBP1 as well as their cellular localisation may be used to predict breast cancer outcome and the benefit from antioestrogen treatments. These factors are indicated to play separate roles in different subtypes of breast cancer, and specific targeting of S6K1 and S6K2 may be valuable in different tumour subtypes, and in comparison to present day’s mTOR inhibitors, further promote individualised therapies, and thereby increase breast cancer survival.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2014. 127 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1388
National Category
Cancer and Oncology
urn:nbn:se:liu:diva-104180 (URN)10.3384/diss.diva-104180 (DOI)978-91-7519-432-5 (print) (ISBN)
Public defence
2014-03-07, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
Available from: 2014-02-10 Created: 2014-02-10 Last updated: 2014-02-10Bibliographically approved

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Karlsson, ElinAhnström, MarieBostner, JosefinePerez-Tenorio, GizehOlsson, BirgitHallbeck, Anna-LottaStål, Olle
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