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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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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.identifier.citation Breast Cancer Research. 2014 May 22;16(3):R49
dc.identifier.uri http://hdl.handle.net/1993/23622
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.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
dc.language.rfc3066 en
dc.description.version Peer Reviewed
dc.rights.holder Anuraag Shrivastav et al.; licensee BioMed Central Ltd.
dc.date.updated 2014-06-11T15:11:18Z
dc.identifier.doi http://dx.doi.org/10.1186/bcr3660


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