Reduced nuclear accumulation of the Ser/Thr protein kinase, RSK2, explains responsiveness to anti-estrogen therapy in patients that have phosphorylation of estrogen receptor alpha at Ser-167

Presentation Number: OR07-2
Date of Presentation: June 15th, 2013

Katarzyna Anna Ludwik* and Deborah Ann Lannigan
Vanderbilt University, Nashville, TN

Abstract

Approximately 65% of breast cancers are estrogen receptor alpha (ERalpha)-positive and are treated with anti-estrogen therapy. However, half of these patients fail to respond to treatment and therefore, there is an ongoing effort to identify better prognostic markers of responsiveness to anti-estrogen therapy. Phosphorylation of ERalpha at Ser-167 (pSer-167) has been found to correlate with longer progression free survival of patients treated with anti-estrogens [3]. Furthermore, in these tumors high levels of pSer-167 positively correlated with active RSK [2]. We have previously found that RSK phosphorylates Ser-167 [1]. We investigated the relationship between active RSK and the responsiveness of ERalpha-positive breast cancer to anti-estrogen therapy. We found that in 25% of ERalpha-positive breast tumors active RSK was localized to the nucleus in regions of high ERalpha expression.  In response to mitogen RSK2 is activated and accumulates in the nucleus of the human breast cell line, MCF-7. Inhibition of RSK activity decreased pSer-167 levels, which indicates that RSK is the predominant kinase that phosphorylates ERalpha.  RSK2 physically associates with ERalpha, and therefore, we determined whether ERalpha could regulate RSK2 nuclear accumulation.  Silencing of ERalpha decreased mitogen-induced RSK2 nuclear accumulation by ~35%.  Similarly, anti-estrogen treatment caused an ~35% decrease in RSK2 nuclear accumulation. Anti-estrogens also decreased the levels of cyclin D1, a potent oncogene, by ~40%. RSK2 silencing or inhibition caused a similar reduction in cyclin D1 expression. Forced RSK2 nuclear localization, achieved by fusing RSK2 with a nuclear localization signal, was sufficient to induce cyclin D1 expression in the absence of mitogen.  Moreover, forced nuclear localization of RSK2 prevented the decrease in cyclin D1 levels caused by 4-hydroxy tamoxifen treatment.  Taken together, these data show that the ERalpha –mediated regulation of cyclin D1 levels occurs through a RSK2-dependent pathway. We propose that patients with high pSer-167 levels have high levels of nuclear RSK2 and that responsiveness to anti-estrogen therapy is a consequence of an ERalpha-dependent decrease in nuclear RSK2 accumulation, which results in reduced cyclin D1 expression and inhibition of tumor growth.

 

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