liu.seSearch for publications in DiVA
Change search
ReferencesLink to record
Permanent link

Direct link
Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit
Linköping University, Department of Clinical and Experimental Medicine, Oncology. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine, Division of Clinical Sciences. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Linköping University, Department of Clinical and Experimental Medicine. Linköping University, Faculty of Health Sciences.
Show others and affiliations
2013 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 137, no 2, 397-406 p.Article in journal (Refereed) Published
Abstract [en]

The frequent alterations of the PI3K/Akt/mTOR-growth signaling pathway are proposed mechanisms for resistance to endocrine therapy in breast cancer, partly through regulation of estrogen receptor alpha (ER) activity. Reliable biomarkers for treatment prediction are required for improved individualized treatment. We performed a retrospective immunohistochemical analysis of primary tumors from 912 postmenopausal patients with node-negative breast cancer, randomized to either tamoxifen or no adjuvant treatment. Phosphorylated (p) Akt-serine (s) 473, p-mTOR-s2448, and ER phosphorylations-s167 and -s305 were evaluated as potential biomarkers of prognosis and tamoxifen treatment efficacy. High expression of p-mTOR indicated a reduced response to tamoxifen, most pronounced in the ER+/progesterone receptor (PgR) + subgroup (tamoxifen vs. no tamoxifen: hazard ratio (HR), 0.86; 95 % confidence interval (CI), 0.31-2.38; P = 0.78), whereas low p-mTOR expression predicted tamoxifen benefit (HR, 0.29; 95 % CI, 0.18-0.49; P = 0.000002). In addition, nuclear p-Akt-s473 as well as p-ER at -s167 and/or -s305 showed interaction with tamoxifen efficacy with borderline statistical significance. A combination score of positive pathway markers including p-Akt, p-mTOR, and p-ER showed significant association with tamoxifen benefit (test for interaction; P = 0.029). Cross-talk between growth signaling pathways and ER-signaling has been proposed to affect tamoxifen response in hormone receptor-positive breast cancer. The results support this hypothesis, as an overactive pathway was significantly associated with reduced response to tamoxifen. A clinical pre-treatment test for cross-talk markers would be a step toward individualized adjuvant endocrine treatment with or without the addition of PI3K/Akt/mTOR pathway inhibitors.

Place, publisher, year, edition, pages
Springer Verlag (Germany) , 2013. Vol. 137, no 2, 397-406 p.
Keyword [en]
mTOR, Akt, Estrogen receptor phosphorylation, Tamoxifen resistance, Immunohistochemistry
National Category
Medical and Health Sciences
URN: urn:nbn:se:liu:diva-88458DOI: 10.1007/s10549-012-2376-yISI: 000313201100007OAI: diva2:604076

Funding Agencies|Swedish Cancer Society||Swedish Research Council||King Gustaf V Jubilee Fund||

Available from: 2013-02-07 Created: 2013-02-07 Last updated: 2014-08-21
In thesis
1. The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations: a crosstalk with potential to predict tamoxifen resistance in breast cancer
Open this publication in new window or tab >>The Akt/mTOR Pathway and Estrogen Receptor Phosphorylations: a crosstalk with potential to predict tamoxifen resistance in breast cancer
2013 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Estrogen receptor α content is the primary breast cancer biomarker distinguishing the patients responsive from the non-responsive to endocrine treatments. Tamoxifen is an estrogen competitor with large potential to treat breast cancer patients and prolongs time to recurrence. Despite the estrogen receptor positivity and tamoxifen treatment, many women face recurrence of the disease. An important mechanism of resistance to endocrine treatments is upregulated growth factor signaling, and the subsequent effect on the estrogen receptor, rendering an active receptor that stimulates cell proliferation or reduced estrogen-receptor dependence.

This thesis concerns the investigation of biomarkers, as a complement to the existing markers, for determining optimal treatment for patients with primary invasive breast cancer. Randomized patient tumor materials were used in order to measure variations in gene copies, proteins, and protein phosphorylations and to further relate these variations to time-to-recurrence. Endocrine untreated groups within the patient tumor sets gave us the opportunity to study the prognostic potential of selected markers and to compare tamoxifen-treated patients with endocrine untreated, thus obtaining a treatment-predictive value of each marker or marker combination.

In endocrine-dependent cancer the 11q13 chromosomal region is frequently amplified, harboring the genes encoding the cell cycle stimulator cyclin D1 and the estrogen receptor phosphorylating kinase Pak1, respectively. Amplification of the genes was associated with reduced time-torecurrence, indicating a prognostic value, whereas PAK1 gene amplification predicted reduced response to tamoxifen treatment. Moreover, the protein expression of Pak1 tended to predict treatment response, which led to the investigation of this protein in a larger cohort. Together with one of its targets, the estrogen receptor phosphorylation at serine 305, Pak1 predicted reduced response to tamoxifen treatment when detected in the nucleus of tumor cells, suggesting activation of this pathway as a mechanism for tamoxifen-treatment resistance. The estrogen receptor is phosphorylated by several growth factor stimulated kinases. The role of serine-167 phosphorylation has been debated, with inconsistent results. To study the biomarker value of this site the upstream activity of Akt, mTOR, and the S6 kinases were analyzed individually and in combinations. As a prognostic factor, serine 167 indicated an improved breast cancer survival, and as a treatment predictive factor we could not detect a significant value of serine 167 as a single marker. However, in combination with serine 305, and Akt/mTOR-pathway activation, the response to tamoxifen treatment was reduced. The mTOR effector protein S6K1 was found to be associated with HER2 positivity and a worse prognosis. In the group of patients with S6K1 accumulation in the tumor cell nuclei, treatment did not prolong time-to-recurrence, similarly as observed with expression of active S6 kinases. In vitro, a simultaneous knockdown of the S6 kinases in estrogen receptor-positive breast cancer cells resulted in G1 arrest, and tamoxifen-induced G1 arrest was in part S6 kinase dependent.

The results presented herein suggest biomarkers that would improve treatment decisions in the clinic, specifically for estrogen receptor-positive breast cancer and tamoxifen treatment but in a broader perspective, also for other endocrine treatments and targeted treatments.

Place, publisher, year, edition, pages
Linköping: Linköping University Electronic Press, 2013. 71 p.
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1379
National Category
Medical and Health Sciences
urn:nbn:se:liu:diva-100903 (URN)10.3384/diss.diva-100903 (DOI)978-91-7519-515-5 (print) (ISBN)
Public defence
2013-12-18, Nils-Holgersalen, ing. 71, Campus US, Linköpings universitet, Linköping, 09:00 (English)
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-12-12Bibliographically approved

Open Access in DiVA

No full text

Other links

Publisher's full text

Search in DiVA

By author/editor
Bostner, JosefineKarlsson, ElinNordenskjöld, BoStål, Olle
By organisation
OncologyFaculty of Health SciencesDivision of Clinical SciencesDepartment of Clinical and Experimental MedicineDepartment of Oncology
In the same journal
Breast Cancer Research and Treatment
Medical and Health Sciences

Search outside of DiVA

GoogleGoogle Scholar
The number of downloads is the sum of all downloads of full texts. It may include eg previous versions that are now no longer available

Altmetric score

Total: 101 hits
ReferencesLink to record
Permanent link

Direct link