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Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Faculty of Health Sciences. Linköping University, Department of Clinical and Experimental Medicine, Oncology.
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: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 128, no 3, 713-723 p.Article in journal (Refereed) Published
Abstract [en]

The mammalian target of rapamycin (mTOR) and its substrates S6K1 and S6K2 regulate cell growth, proliferation, and metabolism through translational control. RPS6KB1 (S6K1) and RPS6KB2 (S6K2) are situated in the commonly amplified 17q21-23 and 11q13 regions. S6K1 amplification and protein overexpression have earlier been associated with a worse outcome in breast cancer, but information regarding S6K2 is scarce. The aim of this study was to evaluate the prognostic and treatment predictive relevance of S6K1/S6K2 gene amplification, as well as S6K2 protein expression in breast cancer. S6K1/S6K2 gene copy number was determined by real-time PCR in 207 stage II breast tumors and S6K2 protein expression was investigated by immunohistochemistry in 792 node-negative breast cancers. S6K1 amplification/gain was detected in 10.7%/21.4% and S6K2 amplification/gain in 4.3%/21.3% of the tumors. S6K2 protein was detected in the nucleus (38%) and cytoplasm (76%) of the tumor cells. S6K1 amplification was significantly associated with HER2 gene amplification and protein expression. S6K2 amplification correlated significantly with high S6K2 mRNA levels, ER+ status and CCND1 amplification. S6K1 and S6K2 gene amplification was associated with a worse prognosis independent of HER2 and CCND1. S6K2 gain and nuclear S6K2 expression was related to an improved benefit from tamoxifen among patients with ER+, respectively ER+/PgR+ tumors. In the ER+/PgR- subgroup, nuclear S6K2 rather indicated decreased tamoxifen responsiveness. S6K1 amplification predicted reduced benefit from radiotherapy. This is the first study showing that S6K2 amplification and overexpression, like S6K1 amplification, have prognostic and treatment predictive significance in breast cancer.

Place, publisher, year, edition, pages
Springer Science Business Media , 2011. Vol. 128, no 3, 713-723 p.
Keyword [en]
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-69784DOI: 10.1007/s10549-010-1058-xISI: 000292557100013OAI: oai:DiVA.org:liu-69784DiVA: diva2:433593
Note
The original publication is available at www.springerlink.com: Gizeh Perez-Tenorio, Elin Karlsson, Marie Ahnström, Birgit Olsson, Birgitta Holmlund, Bo Nordenskjöld, Tommy Fornander, Lambert Skoog and Olle Stål, Clinical potential of the mTOR targets S6K1 and S6K2 in breast cancer, 2011, Breast Cancer Research and Treatment, (128), 3, 713-723. http://dx.doi.org/10.1007/s10549-010-1058-x Copyright: Springer Science Business Media http://www.springerlink.com/Available from: 2011-08-10 Created: 2011-08-08 Last updated: 2017-12-08
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1388
National Category
Cancer and Oncology
Identifiers
urn:nbn:se:liu:diva-104180 (URN)10.3384/diss.diva-104180 (DOI)978-91-7519-432-5 (ISBN)
Public defence
2014-03-07, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (Swedish)
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Supervisors
Available from: 2014-02-10 Created: 2014-02-10 Last updated: 2017-01-11Bibliographically approved

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Perez-Tenorio, GizehKarlsson, ElinAhnström, MarieOlsson, BirgitHolmlund, BirgittaNordenskjöld, BoStål, Olle
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