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Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences.
Karolinska University Hospital.
Karolinska University Hospital.
Linköping University, Department of Clinical and Experimental Medicine, Oncology . Linköping University, Faculty of Health Sciences. Östergötlands Läns Landsting, Centre of Surgery and Oncology, Department of Oncology UHL.
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2010 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 16, no 5, 1624-1633 p.Article in journal (Refereed) Published
Abstract [en]

Purpose: In vitro, p21-activated kinase 1 (Pak1) phosphorylates the serine 305 residue of the estrogen receptor alpha (ER alpha) and influences the response of breast cancer cells to tamoxifen. We investigated the influence of Pak1 and pER alpha(ser305) on breast cancer prognosis and results of tamoxifen therapy. Experimental Design: We examined Pak1 and pER alpha(ser305) protein by immunohistochemistry in a series of 912 tumors from node-negative breast cancer patients randomized to tamoxifen or no adjuvant endocrine treatment. Results: Cytoplasmic Pak1 correlated to large tumors and ER negativity, whereas nuclear Pak1 and pER alpha(ser305) correlated to small tumors and ER positivity. Nuclear expression of Pak1 and pER alpha(ser305) predicted reduced response to tamoxifen in patients with ER alpha-positive tumors (tamoxifen versus no tamoxifen: hazard ratio (HR), 1.33; 95% confidence interval (95% CI), 0.42-4.2; P = 0.63), whereas patients lacking this combination benefitted significantly from tamoxifen (HR, 0.43; 95% CI, 0.30-0.62; P less than 0.0001). Similar nonsignificant trends were detected in analyses of the proteins separately. Pak1 in the cytoplasm was an independent prognostic marker, indicating increased recurrence rate (HR, 1.79; 95% CI, 1.17-2.74; P = 0.0068) and breast cancer mortality (HR, 1.98; 95% CI, 1.14-3.46; P = 0.016) for patients randomized to no adjuvant treatment. Conclusion: Our results suggest that patients with tumors expressing Pak1 and pER alpha(ser305) in combination are a group in which tamoxifen treatment is insufficient. In addition, the pathway may be of interest as a drug target in breast cancer. Furthermore, the findings support previous studies showing that Pak1 has differential roles in the cytoplasm and the nucleus.

Place, publisher, year, edition, pages
American Association for Cancer Research, Inc. , 2010. Vol. 16, no 5, 1624-1633 p.
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:liu:diva-58377DOI: 10.1158/1078-0432.CCR-09-1733ISI: 000278545500030OAI: oai:DiVA.org:liu-58377DiVA: diva2:343308
Note
Original Publication: Josefine Bostner, Lambert Skoog, Tommy Fornander, Bo Nordenskjöld and Olle Stål, Estrogen Receptor-alpha Phosphorylation at Serine 305, Nuclear p21-Activated Kinase 1 Expression, and Response to Tamoxifen in Postmenopausal Breast Cancer, 2010, Clinical Cancer Research, (16), 5, 1624-1633. http://dx.doi.org/10.1158/1078-0432.CCR-09-1733 Copyright: American Association for Cancer Research, Inc. http://www.aacr.org/ Available from: 2010-08-13 Created: 2010-08-11 Last updated: 2017-12-12
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.
Series
Linköping University Medical Dissertations, ISSN 0345-0082 ; 1379
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:liu:diva-100903 (URN)10.3384/diss.diva-100903 (DOI)978-91-7519-515-5 (ISBN)
Public defence
2013-12-18, Nils-Holgersalen, ing. 71, Campus US, Linköpings universitet, Linköping, 09:00 (English)
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Supervisors
Available from: 2013-11-14 Created: 2013-11-14 Last updated: 2013-12-12Bibliographically approved

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