| Title |
Protein Kinase A-induced tamoxifen resistance is mediated by anchoring protein AKAP13
|
|---|---|
| Published in |
BMC Cancer, August 2015
|
| DOI | 10.1186/s12885-015-1591-4 |
| Pubmed ID | |
| Authors |
Cristiane Bentin Toaldo, Xanthippi Alexi, Karin Beelen, Marleen Kok, Michael Hauptmann, Maurice Jansen, Els Berns, Jacques Neefjes, Sabine Linn, Rob Michalides, Wilbert Zwart |
| Abstract |
Estrogen Receptor alpha (ERα)-positive breast cancer patients receive endocrine therapy, often in the form of tamoxifen. However, resistance to tamoxifen is frequently observed. A signalling cascade that leads to tamoxifen resistance is dictated by activation of the Protein Kinase A (PKA) pathway, which leads to phosphorylation of ERα on Serine 305 and receptor activation, following tamoxifen binding. Thus far, it remains elusive what protein complexes enable the PKA-ERα interaction resulting in ERα Serine 305 phosphorylation. We performed immunohistochemistry to detect ERαSerine 305 phosphorylation in a cohort of breast cancer patients who received tamoxifen treatment in the metastatic setting. From the same tumor specimens, Agilent 44 K gene expression analyses were performed and integrated with clinicopathological data and survival information. In vitro analyses were performed using MCF7 breast cancer cells, which included immunoprecipitations and Fluorescence Resonance Energy Transfer (FRET) analyses to illustrate ERα complex formation. siRNA mediated knockdown experiments were performed to assess effects on ERαSerine 305 phosphorylation status, ERα/PKA interactions and downstream responsive gene activity. Stratifying breast tumors on ERα Serine 305 phosphorylation status resulted in the identification of a gene network centered upon AKAP13. AKAP13 mRNA expression levels correlate with poor outcome in patients who received tamoxifen treatment in the metastatic setting. In addition, AKAP13 mRNA levels correlate with ERαSerine 305 phosphorylation in breast tumor samples, suggesting a functional connection between these two events. In a luminal breast cancer cell line, AKAP13 was found to interact with ERα as well as with a regulatory subunit of PKA. Knocking down of AKAP13 prevented PKA-mediated Serine 305 phosphorylation of ERα and abrogated PKA-driven tamoxifen resistance, illustrating that AKAP13 is an essential protein in this process. We show that the PKA-anchoring protein AKAP13 is essential for the phosphorylation of ERαS305, which leads to tamoxifen resistance both in cell lines and tamoxifen-treated breast cancer patients. |
X Demographics
The data shown below were collected from the profiles of 5 X users who shared this research output. Click here to find out more about how the information was compiled.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Netherlands | 1 | 20% |
| United States | 1 | 20% |
| Unknown | 3 | 60% |
Demographic breakdown
| Type | Count | As % |
|---|---|---|
| Members of the public | 3 | 60% |
| Scientists | 1 | 20% |
| Practitioners (doctors, other healthcare professionals) | 1 | 20% |
Mendeley readers
The data shown below were compiled from readership statistics for 23 Mendeley readers of this research output. Click here to see the associated Mendeley record.
Geographical breakdown
| Country | Count | As % |
|---|---|---|
| Netherlands | 1 | 4% |
| Germany | 1 | 4% |
| Unknown | 21 | 91% |
Demographic breakdown
| Readers by professional status | Count | As % |
|---|---|---|
| Student > Ph. D. Student | 6 | 26% |
| Researcher | 5 | 22% |
| Student > Master | 2 | 9% |
| Student > Bachelor | 1 | 4% |
| Professor > Associate Professor | 1 | 4% |
| Other | 1 | 4% |
| Unknown | 7 | 30% |
| Readers by discipline | Count | As % |
|---|---|---|
| Biochemistry, Genetics and Molecular Biology | 7 | 30% |
| Agricultural and Biological Sciences | 4 | 17% |
| Medicine and Dentistry | 3 | 13% |
| Chemistry | 1 | 4% |
| Unknown | 8 | 35% |
Attention Score in Context
This research output has an Altmetric Attention Score of 3. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 18 August 2015.
All research outputs
#12,738,978
of 22,821,814 outputs
Outputs from BMC Cancer
#2,650
of 8,301 outputs
Outputs of similar age
#114,153
of 264,379 outputs
Outputs of similar age from BMC Cancer
#37
of 147 outputs
Altmetric has tracked 22,821,814 research outputs across all sources so far. This one is in the 43rd percentile – i.e., 43% of other outputs scored the same or lower than it.
So far Altmetric has tracked 8,301 research outputs from this source. They receive a mean Attention Score of 4.3. This one has gotten more attention than average, scoring higher than 67% of its peers.
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We're also able to compare this research output to 147 others from the same source and published within six weeks on either side of this one. This one has gotten more attention than average, scoring higher than 74% of its contemporaries.