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Extranuclear Coactivator Signaling Confers Insensitivity to Tamoxifen.

Kumar, Rakesh; Zhang, Hao; Wigerup, Caroline LU ; Vadlamudi, Ratna K; Landberg, Göran LU and Rayala, Suresh K (2009) In Clinical Cancer Research 15. p.4123-4130
Abstract
PURPOSE: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-alpha-positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.EXPERIMENTAL DESIGN: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid-, and... (More)
PURPOSE: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-alpha-positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.EXPERIMENTAL DESIGN: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness.RESULTS: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1.CONCLUSIONS: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Clinical Cancer Research
volume
15
pages
4123 - 4130
publisher
American Association for Cancer Research
external identifiers
  • wos:000267080800027
  • pmid:19470742
  • scopus:67449123308
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-08-2347
language
English
LU publication?
yes
id
0f92f901-7b8b-4704-913d-a654c844aabb (old id 1412006)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/19470742?dopt=Abstract
date added to LUP
2009-06-03 16:03:28
date last changed
2017-10-01 04:57:02
@article{0f92f901-7b8b-4704-913d-a654c844aabb,
  abstract     = {PURPOSE: Tamoxifen is one of many standard therapeutic options currently available for estrogen receptor-alpha-positive breast cancer patients. Emerging data have suggested that levels of estrogen receptor coregulatory proteins play a significant role in acquiring resistance to antiestrogen action. It has been suggested that high levels of estrogen receptor coactivators and its mislocalization may enhance the estrogen agonist activity of tamoxifen and contribute to tamoxifen resistance.EXPERIMENTAL DESIGN: In an effort to understand the impact of nongenomic signaling and its contribution to hormone resistance in a whole-animal setting, we generated a transgenic mouse expressing a cytoplasmic version of proline-, glutamic acid-, and leucine-rich protein-1 (PELP1) mutant defective in its nuclear translocation (PELP1-cyto) and implanted these mice with tamoxifen pellets to assess its responsiveness.RESULTS: We show that mammary glands from these mice developed widespread hyperplasia with increased cell proliferation and enhanced activation of mitogen-activated protein kinase and AKT as early as 12 weeks of age. Treatment with tamoxifen did not inhibit this hyperplasia; instead, such treatment exaggerated hyperplasia with an enhanced degree of alteration, indicative of hypersensitivity to tamoxifen. Analysis of molecular markers in the transgenic mammary glands from the tamoxifen-treated transgenic mice showed higher levels of proliferation markers proliferating cell nuclear antigen and activated mitogen-activated protein kinase than in untreated PELP1-cyto cell-derived mice. We also found that nude mice with MCF-7/PELP1-cyto cell-derived tumor xenografts did not respond to tamoxifen. Using immunohistochemical analysis, we found that 43% of human breast tumor samples had high levels of cytoplasmic PELP1, which shows a positive correlation between tumor grade and proliferation. Patients whose tumors had high levels of cytoplasmic PELP1 exhibited a tendency to respond poorly to tamoxifen compared with patients whose tumors had low levels of cytoplasmic PELP1.CONCLUSIONS: These findings suggest that PELP1 localization could be used as a determinant of hormone sensitivity or vulnerability. The establishment of the PELP1-cyto transgenic mouse model is expected to facilitate the development of preclinical approaches for effective intervention of breast tumors using cytoplasmic coregulators and active nongenomic signaling.},
  author       = {Kumar, Rakesh and Zhang, Hao and Wigerup, Caroline and Vadlamudi, Ratna K and Landberg, Göran and Rayala, Suresh K},
  issn         = {1078-0432},
  language     = {eng},
  pages        = {4123--4130},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Extranuclear Coactivator Signaling Confers Insensitivity to Tamoxifen.},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-08-2347},
  volume       = {15},
  year         = {2009},
}