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01-01-2010 | Preclinical Study

Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor α and its phosphorylation at serine 305

Authors: Cinzia Giordano, Yukun Cui, Ines Barone, Sebastiano Ando, Michael A. Mancini, Valeria Berno, Suzanne A. W. Fuqua

Published in: Breast Cancer Research and Treatment | Issue 1/2010

Abstract

Estrogens play a crucial role in breast tumor growth, which is the rationale for the use of antiestrogens, such as tamoxifen, in women with estrogen receptor (ER)-α-positive breast cancer. However, hormone resistance is a major clinical problem. Altered growth factor signaling to the ERα pathway has been shown to be associated with the development of clinical resistance. We previously have identified a mutation that replaces arginine for lysine at residue 303 (K303R) of ERα, which confers hypersensitive growth in low levels of estrogen. To determine if the K303R mutation could participate in the evolution of hormone resistance, we generated MCF-7 breast cancer cells stably transfected with either wild-type (WT) or K303R ERα. We found that the mutation confers decreased sensitivity to tamoxifen in the presence of the growth factor heregulin, using anchorage-independent growth assays. K303R ERα-expressing cells were hypersensitive to growth factor signals. Our data suggest that phosphorylation of serine 305 within the hinge domain of ERα might play a key role in increasing ligand-independent activity of the mutant receptor. We hypothesize that the mutation adapts the receptor for enhanced bidirectional cross-talk with the HER2 growth factor receptor pathway, which then impacts on responsiveness to tamoxifen.

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Title: Growth factor-induced resistance to tamoxifen is associated with a mutation of estrogen receptor α and its phosphorylation at serine 305
Authors: Cinzia Giordano
Yukun Cui
Ines Barone
Sebastiano Ando
Michael A. Mancini
Valeria Berno
Suzanne A. W. Fuqua
Publication date: 01-01-2010
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2010
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-009-0334-0

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