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Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance.

Busch, Susann; Sims, Andrew H.; Stal, Olle; Fernö, Mårten LU and Landberg, Goran (2015) In Cancer Research 75(7). p.1457-1469
Abstract
One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer.... (More)
One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease. (C)2015 AACR. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Cancer Research
volume
75
issue
7
pages
1457 - 1469
publisher
American Association for Cancer Research Inc.
external identifiers
  • wos:000351948900031
  • scopus:84942921697
  • pmid:25833830
ISSN
1538-7445
DOI
10.1158/0008-5472.CAN-14-1583
language
English
LU publication?
yes
id
86af1da8-2df2-4978-b62b-c726dca20031 (old id 5277774)
date added to LUP
2015-05-04 08:57:30
date last changed
2017-02-26 03:48:39
@article{86af1da8-2df2-4978-b62b-c726dca20031,
  abstract     = {One third of the patients with estrogen receptor alpha (ER alpha)-positive breast cancer who are treated with the antiestrogen tamoxifen will either not respond to initial therapy or will develop drug resistance. Endocrine response involves crosstalk between ER alpha and TGF beta signaling, such that tamoxifen non-responsiveness or resistance in breast cancer might involve aberrant TGF beta signaling. In this study, we analyzed TGF beta receptor type 2 (TGFBR2) expression and correlated it with ER alpha status and phosphorylation in a cohort of 564 patients who had been randomized to tamoxifen or no-adjuvant treatment for invasive breast carcinoma. We also evaluated an additional four independent genetic datasets in invasive breast cancer. In all the cohorts we analyzed, we documented an association of low TGFBR2 protein and mRNA expression with tamoxifen resistance. Functional investigations confirmed that cell cycle or apoptosis responses to estrogen or tamoxifen in ER alpha-positive breast cancer cells were impaired by TGFBR2 silencing, as was ER alpha phosphorylation, tamoxifen-induced transcriptional activation of TGF beta, and upregulation of the multidrug resistance protein ABCG2. Acquisition of low TGFBR2 expression as a contributing factor to endocrine resistance was validated prospectively in a tamoxifen-resistant cell line generated by long-term drug treatment. Collectively, our results established a central contribution of TGF beta signaling in endocrine resistance in breast cancer and offered evidence that TGFBR2 can serve as an independent biomarker to predict treatment outcomes in ER alpha-positive forms of this disease. (C)2015 AACR.},
  author       = {Busch, Susann and Sims, Andrew H. and Stal, Olle and Fernö, Mårten and Landberg, Goran},
  issn         = {1538-7445},
  language     = {eng},
  number       = {7},
  pages        = {1457--1469},
  publisher    = {American Association for Cancer Research Inc.},
  series       = {Cancer Research},
  title        = {Loss of TGFβ Receptor Type 2 Expression Impairs Estrogen Response and Confers Tamoxifen Resistance.},
  url          = {http://dx.doi.org/10.1158/0008-5472.CAN-14-1583},
  volume       = {75},
  year         = {2015},
}