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Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer

Busch, Susann; Rydén, Lisa LU ; Stal, Olle; Jirström, Karin LU and Landberg, Göran LU (2012) In PLoS ONE 7(9).
Abstract
Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not... (More)
Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. Conclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
PLoS ONE
volume
7
issue
9
publisher
Public Library of Science
external identifiers
  • wos:000309554700056
  • scopus:84866703356
ISSN
1932-6203
DOI
10.1371/journal.pone.0045669
language
English
LU publication?
yes
id
05263acf-8c69-4f9f-b466-a28c11e01667 (old id 3184335)
date added to LUP
2012-12-03 06:55:22
date last changed
2017-07-02 04:08:24
@article{05263acf-8c69-4f9f-b466-a28c11e01667,
  abstract     = {Purpose: The aim of this study was to evaluate ERK phosphorylation as a stromal biomarker for breast cancer prognosis and tamoxifen treatment prediction within a randomized tamoxifen trial. Patients and Methods: Tissue microarrays of two breast cancer cohorts including in total 743 invasive breast cancer samples were analyzed for ERK phosphorylation (pERK) and smooth muscle actin-alpha expression (SMA alpha) in cancer-associated fibroblasts (CAFs) and links to clinico-pathological data and treatment-predictive values were delineated. Results: By analyzing a unique randomized tamoxifen trial including breast cancer patients receiving no adjuvant treatment we show for the first time that patients low in ERK phosphorylation in CAFs did not respond to tamoxifen treatment despite having estrogen-receptor alpha (ER alpha-positive tumors compared to patients with high pERK levels in CAFs (P = 0.015, multivariate Cox regression interaction analysis). In both clinical materials we further show a significant association between pERK and SMA alpha, a characteristic marker for activated fibroblasts. SMA alpha expression however was not linked to treatment-predictive information but instead had prognostic qualities. Conclusion: The data suggests that the presence of a subpopulation of CAFs, defined by minimal activated ERK signaling, is linked to an impaired tamoxifen response. Thus, this report illustrates the importance of the stroma for monitoring treatment effects in pre-menopausal breast cancer.},
  author       = {Busch, Susann and Rydén, Lisa and Stal, Olle and Jirström, Karin and Landberg, Göran},
  issn         = {1932-6203},
  language     = {eng},
  number       = {9},
  publisher    = {Public Library of Science},
  series       = {PLoS ONE},
  title        = {Low ERK Phosphorylation in Cancer-Associated Fibroblasts Is Associated with Tamoxifen Resistance in Pre-Menopausal Breast Cancer},
  url          = {http://dx.doi.org/10.1371/journal.pone.0045669},
  volume       = {7},
  year         = {2012},
}