Phosphorylation of ERα at serine 118 in primary breast cancer and in tamoxifen-resistant tumours is indicative of a complex role for ERα phosphorylation in breast cancer progression

Abstract

Oestrogen receptor-a (ERa) is an important prognostic marker in breast cancer and endocrine therapies are designed to inhibit or prevent ERa activity. In vitro studies have indicated that phosphorylation of ERa, in particular on serine 118 (S118), can result in activation in a ligandindependent manner, thereby potentially contributing to resistance to endocrine agents, such as tamoxifen and aromatase inhibitors. Here we report the immunohistochemistry (IHC) of S118 phosphorylation in 301 primary breast tumour biopsies. Surprisingly, this analysis shows that S118 phosphorylation is higher in more differentiated tumours, suggesting that phosphorylation at this site is associated with a good prognosis in patients not previously treated with endocrine agents. However, we also report that S118 phosphorylation was elevated in tumour biopsies taken from patients who had relapsed following tamoxifen treatment, when compared to pre-treatment biopsies. Taken together, these data are consistent with the view that S118 phosphorylation is a feature of normal ERa function and that increases in levels of phosphorylation at this site may play a key role in the emergence of endocrine resistance in breast cancer.

Transient over-expression of estrogen receptor-α in breast cancer cells promotes cell survival and estrogen-independent growth

“…In this context, elevated HER2 and EGFR expression have been observed in cell line models of tamoxifen resistance, whilst elevated ERK1/2 MAPK [7] and high levels of phosphorylated AKT have been associated with poor response to tamoxifen and a worse patient prognosis [8]. Further, phosphorylation of ERα at serine 118 (S118) is elevated in recurrence following tamoxifen treatment [9]. Finally, high-level expression of the coactivator AIB1 is associated with poor response to tamoxifen in ERα-positive breast cancer, with AIB1-and HER2-positive patients having the worst outcome following tamoxifen treatment [10].…”

MGMT Inhibition Restores ERα Functional Sensitivity to Antiestrogen Therapy

“…Roughly, 70% of human breast tumors express significant levels of estrogen receptor alpha (ERα) (1), making antiestrogen therapy an important therapeutic modality in breast cancer treatment (2)(3)(4) There is extensive data supporting various correlations between ERα phosphorylation patterns and sensitivity to antiestrogen therapy and clinical indicators of treatment response (delayed disease progression/ improved survival) (6)(7)(8)(9)(10). ERα phosphorylation of serine residues in the activation domain function 1 (AF-1) leads to enhanced ERα-driven transcription via modulation of coactivators recruitment.…”

IL6 induces TAM resistance via kinase-specific phosphorylation of ERα in OVCA cells

“…Sarwar et al (2006) demonstrated that pERa-Ser118 was elevated in tumor biopsies taken from patients who had relapsed following TAM treatment. Yamashita et al (2008) revealed that a higher expression of pERa-Ser118 was a predictor of poorer survival.…”

“…EGFR, HER2, and IGF1R) (Gee et al 2005, Nicholson et al 2007, Moerkens et al 2014). In addition, increased activation of their downstream targets ERK and PI3K/Akt leading to increased pERa-Ser118 and/or pERa-Ser167 have been observed (Gee et al 2001, Yamashita et al 2005, Sarwar et al 2006. It has been widely reported that IL6 plays a critical role in the development and progression of OVCA (Syed et al 2002, Nilsson et al 2005, Rabinovich et al 2007, Yang et al 2009, Wang et al 2012.…”

“…Subsequently, we demonstrated that both exogenous (a relatively short period of treatment with recombinant IL6) and endogenous IL6 (as a result of transfection with plasmid encoding sense IL6) enhance expression of pERa-Ser118:total ERa and pERa-Ser167:total ERa in non-IL6-expressing A2780 cells, while deleting the endogenous IL6 expression in IL6-overexpressing CAOV-3 cells (due to transfection with plasmid encoding antisense IL6) reduces expression of pERa-Ser118:total ERa and pERa-Ser167:total ERa. Phosphorylation of ERa-Ser118 and ERa-Ser167 are two sites which have been shown to be involved in TAM resistance (Sarwar et al 2006, Yamashita et al 2008, Yamnik et al 2009, Guo et al 2010; we recently showed that there was a significantly increased resistance to TAM in A2780 cells pretreated with IL6 (A2780/preIL6) and ssIL6-transfected A2780 cells and a markedly increased responsiveness to TAM in asIL6-transfected CAOV-3 cells as compared with the corresponding control cells (Wang et al 2014). These findings indicate that IL6-induced TAM resistance may also be associated with increased expression of pERaSer118 and pERa-Ser167 in OVCA cells.…”