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Estrogen receptor ? represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity.

ABSTRACT:

Introduction

The inhibition of estrogen receptor (ER) ? action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ER? in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ER? can modulate pathways implicated in endocrine resistance development.

Methods

T47-D and MCF-7 ER?-expressing breast cancer cells with tetracycline-regulated expression of ER? were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit.

Results

Expression of ER? in ER?-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ER?. Furthermore, ER? increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ER? expression increased the sensitivity of these breast cancer cells to tamoxifen.

Conclusions

Our results suggest a link between expression of ER? and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ER? presence in breast cancer samples is an indicator for endocrine response. Current therapies in ER?-positive breast cancers aim to impair ER? activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ER? as a target in selected groups of breast cancer.

SUBMITTER: Lindberg K

PROVIDER: S-EPMC3219206 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature

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Publications

Estrogen receptor β represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity.

Lindberg Karolina K Helguero Luisa A LA Omoto Yoko Y Gustafsson Jan-Åke JÅ Haldosén Lars-Arne LA

Breast cancer research : BCR 20110414 2

<h4>Introduction</h4>The inhibition of estrogen receptor (ER) α action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ERβ in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ERβ can modulate pathways implicated in endocrine resistance ...[more]

PMID: 21492444

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