Advanced

PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer

Bosch Campos, Ana LU ; Li, Zhiqiang; Bergamaschi, Anna; Ellis, Haley; Toska, Eneda; Prat, Aleix; Tao, Jessica J.; Spratt, Daniel E.; Viola-Villegas, Nerissa T. and Castel, Pau, et al. (2015) In Science Translational Medicine 7(283). p.1-11
Abstract

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein... (More)

Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.

(Less)
Please use this url to cite or link to this publication:
author
, et al. (More)
(Less)
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Science Translational Medicine
volume
7
issue
283
pages
1 - 11
publisher
American Association for the Advancement of Science (AAAS)
external identifiers
  • scopus:84928186818
ISSN
1946-6234
DOI
10.1126/scitranslmed.aaa4442
language
English
LU publication?
yes
id
0d04ca85-9314-4f2f-a56d-aca6f0104663
date added to LUP
2016-12-02 15:29:41
date last changed
2017-11-19 04:35:29
@article{0d04ca85-9314-4f2f-a56d-aca6f0104663,
  abstract     = {<p>Activating mutations of PIK3CA are the most frequent genomic alterations in estrogen receptor (ER)-positive breast tumors, and selective phosphatidylinositol 3-kinase a (PI3Kα) inhibitors are in clinical development. The activity of these agents, however, is not homogeneous, and only a fraction of patients bearing PIK3CA-mutant ER-positive tumors benefit from single-agent administration. Searching for mechanisms of resistance, we observed that suppression of PI3K signaling results in induction of ER-dependent transcriptional activity, as demonstrated by changes in expression of genes containing ER-binding sites and increased occupancy by the ER of promoter regions of upregulated genes. Furthermore, expression of ESR1 mRNA and ER protein were also increased upon PI3K inhibition. These changes in gene expression were confirmed in vivo in xenografts and patient-derived models and in tumors from patients undergoing treatment with the PI3Kα inhibitor BYL719. The observed effects on transcription were enhanced by the addition of estradiol and suppressed by the anti-ER therapies fulvestrant and tamoxifen. Fulvestrant markedly sensitized ER-positive tumors to PI3Kα inhibition, resulting in major tumor regressions in vivo. We propose that increased ER transcriptional activity may be a reactive mechanism that limits the activity of PI3K inhibitors and that combined PI3K and ER inhibition is a rational approach to target these tumors.</p>},
  articleno    = {283ra51},
  author       = {Bosch Campos, Ana and Li, Zhiqiang and Bergamaschi, Anna and Ellis, Haley and Toska, Eneda and Prat, Aleix and Tao, Jessica J. and Spratt, Daniel E. and Viola-Villegas, Nerissa T. and Castel, Pau and Minuesa, Gerard and Morse, Natasha and Rodón, Jordi and Ibrahim, Yasir and Cortes, Javier and Perez-Garcia, Jose and Galvan, Patricia and Grueso, Judit and Guzman, Marta and Katzenellenbogen, John A. and Kharas, Michaelz and Lewis, Jason S. and Dickler, Maura and Serra, Violeta and Rosen, Neal and Chandarlapaty, Sarat and Scaltriti, Maurizio and Baselga, José},
  issn         = {1946-6234},
  language     = {eng},
  month        = {04},
  number       = {283},
  pages        = {1--11},
  publisher    = {American Association for the Advancement of Science (AAAS)},
  series       = {Science Translational Medicine},
  title        = {PI3K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer},
  url          = {http://dx.doi.org/10.1126/scitranslmed.aaa4442},
  volume       = {7},
  year         = {2015},
}