Low phosphorylation of estrogen receptor   (ER ) serine 118 and high phosphorylation of ER  serine 167 improve survival in ER-positive breast cancer

Abstract

Endocrine therapy has become the most important treatment option for women with estrogen receptor (ER)-positive breast cancer. Urgently needed are prognostic assays that can identify those who need additional adjuvant therapy, such as signal transduction inhibitors or chemotherapy, for ER-positive early breast cancer. We examined phosphorylation of ERa serine (Ser) 118, ERa Ser167, p44/42 mitogen-activated protein kinase (MAPK), and Akt and expression of progesterone receptor, amplified in breast cancer 1 (AIB1), human epidermal growth factor receptor 2 (HER2), p53, and Ki67 in ER-positive breast cancers by immunohistochemistry, and analyzed their significance for prognosis. Phosphorylation levels of ERa Ser118, ERa Ser167, MAPK, and Akt were positively correlated. AIB1 expression was significantly associated with phosphorylation of ERa Ser118, MAPK, and Akt, and HER2 expression. Low phosphorylation of ERa Ser118 and high phosphorylation of ERa Ser167 were associated with significantly improved disease-free (PZ0.0003 and PZ0.0002 respectively) and overall survival (PZ0.0007 and PZ0.0016 respectively) in multivariate analyses. Our data suggest that phosphorylation of ERa Ser118 and ERa Ser167 affects survival in ER-positive breast cancer and could be helpful in distinguishing patients who are likely to benefit from endocrine therapy alone from those who are not.

Targeting the receptor tyrosine kinase RET sensitizes breast cancer cells to tamoxifen treatment and reveals a role for RET in endocrine resistance

“…In particular, phosphorylation of Ser118 and Ser167 in the AF1 domain of ERa drive estrogen-independent transcriptional activation and are associated with resistance to endocrine therapy. For example, HER2 overexpression results in ERa phosphorylation and resistance to tamoxifen treatment in vitro (Shou et al, 2004;Pancholi et al, 2008) and it is associated with resistance to endocrine therapy in vivo (Benz et al, 1992;Yamashita et al, 2008;Kok et al, 2009). In spite of this the molecular mechanisms governing resistance to endocrine therapy remains largely unclear.…”

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

“…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.…”

“…The results of previous studies in vivo and in vitro remain conflicting regarding whether pERa-Ser118 or pERa-Ser167 have an effect on TAM resistance (Mintz et al 2008, Yamashita et al 2008, Guo et al 2010, Motomura et al 2010, Chen et al 2013. Sarwar et al (2006) demonstrated that pERa-Ser118 was elevated in tumor biopsies taken from patients who had relapsed following TAM treatment.…”

“…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. Recently, Chen et al (2013) examined 104 patients with primary breast cancer who had received adjuvant TAM therapy and found that pERa-Ser118, but not pERa-Ser167, was significantly correlated with a shorter survival time and predicted breast cancer resistance to TAM.…”

“…Other studies have also demonstrated that pERa-Ser167 has an effect on the survival of breast cancer patients. Results of a study by Yamashita et al (2008) indicated that a higher expression of pERa-Ser167 was correlated with improved survival in ER-positive breast cancer cases. However, Guo et al (2010) demonstrated that ERa-Ser167 was phosphorylated by IKK3 in vitro and in vivo, leading to the upregulation of cyclin D1 and resulting in TAM resistance.…”