dc.contributor.author	Shrivastav, Anuraag
dc.contributor.author	Bruce, Mary C
dc.contributor.author	Jaksic, Danira
dc.contributor.author	Bader, Tarek
dc.contributor.author	Seekallu, Srinivas
dc.contributor.author	Penner, Carla
dc.contributor.author	Nugent, Zoann
dc.contributor.author	Watson, Peter
dc.contributor.author	Murphy, Leigh
dc.date.accessioned	2014-06-11T15:11:18Z
dc.date.available	2014-06-11T15:11:18Z
dc.date.issued	2014-05-22
dc.date.updated	2014-06-11T15:11:18Z
dc.description.abstract	Abstract Introduction A phosphorylation score for estrogen receptor-alpha (ERα), called P7 score, was shown previously to be an independent prognostic factor in breast cancer patients treated with tamoxifen. Since mechanistic target of rapamycin (mTOR) activation is implicated in resistance to endocrine therapy in breast cancer we determined whether mechanistic target of rapamycin complex 1 (mTORC1) activation, measured by phosphorylation on S2448 (p-mTOR), was associated with the P7-score and/or clinical outcome in the same cohort. Methods mTOR phosphorylation status was determined at S2448 residue in vivo by immunohistochemistry in a cohort of more than 400 well-characterized ERα positive breast tumors. MCF7 cells were treated with estrogen and activation of mTOR pathway was determined by Western blotting. Results Contrary to earlier reports, p-mTOR expression, measured by immunohistochemistry, was negatively associated with size and nodal status. Additionally, p-S2448 mTOR expression was positively correlated with p-S118- ERα, p-S167-ERα and p-S282-ERα but negatively correlated with p-T311- ERα. Consistent with these, p-S2448 mTOR was negatively associated with P7-score and was significantly associated with overall survival (OS) (hazard ratio (HR) = 0.61, P = 0.028, 95% confidence interval (CI) 0.39 to 0.95, n = 337) and relapse-free survival (HR = 0.58, P = 0.0032, 95% CI 0.41 to 0.83, n = 337) following univariate but not multivariate analysis. Furthermore, we show that estrogen can regulate phosphorylation of mTOR and its down stream target p70S6 kinase. Additionally, recombinant mTOR can phosphorylate ERα in vitro. Conclusions These data suggest that in breast tumors where there is intact estrogen regulated signaling, mTOR is regulated by estrogen and therefore associated with an increased likelihood of responsiveness to endocrine therapy.
dc.description.version	Peer Reviewed
dc.identifier.citation	Breast Cancer Research. 2014 May 22;16(3):R49
dc.identifier.doi	http://dx.doi.org/10.1186/bcr3660
dc.identifier.uri	http://hdl.handle.net/1993/23622
dc.language.rfc3066	en
dc.rights	open access	en_US
dc.rights.holder	Anuraag Shrivastav et al.; licensee BioMed Central Ltd.
dc.title	The mechanistic target for rapamycin pathway is related to the phosphorylation score for estrogen receptor-α in human breast tumors in vivo
dc.type	Journal Article

The mechanistic target for rapamycin pathway is related to the phosphorylation score for estrogen receptor-α in human breast tumors in vivo

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