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The mTOR effectors 4EBP1 and S6K2 are frequently coexpressed, and associated with a poor prognosis and endocrine resistance in breast cancer: a retrospective study including patients from the randomised Stockholm tamoxifen trials.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
Linköpings universitet, Institutionen för klinisk och experimentell medicin, Avdelningen för kliniska vetenskaper. Linköpings universitet, Hälsouniversitetet. Östergötlands Läns Landsting, Centrum för kirurgi, ortopedi och cancervård, Onkologiska kliniken US.
Vise andre og tillknytning
2013 (engelsk)Inngår i: Breast Cancer Research, ISSN 1465-5411, E-ISSN 1465-542X, Vol. 15, nr 5, s. R96-Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

INTRODUCTION: mTOR and its downstream effectors the 4E-binding protein 1 (4EBP1) and the p70 ribosomal S6 kinases (S6K1 and S6K2) are frequently upregulated in breast cancer, and assumed to be driving forces in tumourigenesis, in close connection with oestrogen receptor (ER) networks. Here, we investigated these factors as clinical markers in five different cohorts of breast cancer patients.

METHODS: The prognostic significance of 4EBP1, S6K1 and S6K2 mRNA expression was assessed with real-time PCR in 93 tumours from the treatment randomised Stockholm trials, encompassing postmenopausal patients enrolled between 1976 and 1990. Three publicly available breast cancer cohorts were used to confirm the results. Furthermore, the predictive values of 4EBP1 and p4EBP1_S65 protein expression for both prognosis and endocrine treatment benefit were assessed by immunohistochemical analysis of 912 node-negative breast cancers from the Stockholm trials.

RESULTS: S6K2 and 4EBP1 mRNA expression levels showed significant correlation and were associated with a poor outcome in all cohorts investigated. 4EBP1 protein was confirmed as an independent prognostic factor, especially in progesterone receptor (PgR)-expressing cancers. 4EBP1 protein expression was also associated with a poor response to endocrine treatment in the ER/PgR positive group. Cross-talk to genomic as well as non-genomic ER/PgR signalling may be involved and the results further support a combination of ER and mTOR signalling targeted therapies.

CONCLUSION: This study suggests S6K2 and 4EBP1 as important factors for breast tumourigenesis, interplaying with hormone receptor signalling. We propose S6K2 and 4EBP1 as new potential clinical markers for prognosis and endocrine therapy response in breast cancer.

sted, utgiver, år, opplag, sider
BioMed Central , 2013. Vol. 15, nr 5, s. R96-
Emneord [en]
mTOR; S6 kinase; 17q21-23; 11q13; Gene amplification; Tamoxifen response
HSV kategori
Identifikatorer
URN: urn:nbn:se:liu:diva-104178DOI: 10.1186/bcr3557ISI: 000329763800024PubMedID: 24131622OAI: oai:DiVA.org:liu-104178DiVA, id: diva2:695094
Tilgjengelig fra: 2014-02-10 Laget: 2014-02-10 Sist oppdatert: 2017-12-06bibliografisk kontrollert
Inngår i avhandling
1. Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
Åpne denne publikasjonen i ny fane eller vindu >>Clinical potential of the mTOR effectors S6K1, S6K2 and 4EBP1 in breast cancer
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Linköping: Linköping University Electronic Press, 2014. s. 127
Serie
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1388
HSV kategori
Identifikatorer
urn:nbn:se:liu:diva-104180 (URN)10.3384/diss.diva-104180 (DOI)978-91-7519-432-5 (ISBN)
Disputas
2014-03-07, Eken, Campus US, Linköpings universitet, Linköping, 09:00 (svensk)
Opponent
Veileder
Tilgjengelig fra: 2014-02-10 Laget: 2014-02-10 Sist oppdatert: 2019-11-19bibliografisk kontrollert

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