American Association for Cancer Research
10780432ccr143277-sup-142588_1_supp_3043064_nqttgq.xlsx (141.26 kB)

Table S6 from SRC3 Phosphorylation at Serine 543 Is a Positive Independent Prognostic Factor in ER-Positive Breast Cancer

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posted on 2023-03-31, 18:51 authored by Wilbert Zwart, Koen D. Flach, Bharath Rudraraju, Tarek M.A. Abdel-Fatah, Ondrej Gojis, Sander Canisius, David Moore, Ekaterina Nevedomskaya, Mark Opdam, Marjolein Droog, Ingrid Hofland, Steve Chan, Jacqui Shaw, Ian O. Ellis, R. Charles Coombes, Jason S. Carroll, Simak Ali, Carlo Palmieri

Motif analyses for chromatin binding sites shared or selectively enriched for SRC3-pS543 and ER� in tumor #1.



Purpose: The steroid receptor coactivator SRC3 is essential for the transcriptional activity of estrogen receptor α (ERα). SRC3 is sufficient to cause mammary tumorigenesis, and has also been implicated in endocrine resistance. SRC3 is posttranslationally modified by phosphorylation, but these events have not been investigated with regard to functionality or disease association. Here, we investigate the spatial selectivity of SRC3-pS543/DNA binding over the human genome and its expression in primary human breast cancer in relation with outcome.Experimental Design: Chromatin immunoprecipitation, coupled with sequencing, was used to determine the chromatin binding patterns of SRC3-pS543 in the breast cancer cell line MCF7 and two untreated primary breast cancers. IHC was used to assess the expression of SRC3 and SRC3-pS543 in 1,650 primary breast cancers. The relationship between the expression of SRC3 and SRC3-pS543, disease-free survival (DFS), and breast cancer specific survival (BCSS) was assessed.Results: Although total SRC3 is selectively found at enhancer regions, SRC3-pS543 is recruited to promoters of ERα responsive genes, both in the MCF7 cell line and primary breast tumor specimens. SRC3-pS543 was associated with both improved DFS (P = 0.003) and BCSS (P = 0.001) in tamoxifen untreated high-risk patients, such a correlation was not seen in tamoxifen-treated cases, the interaction was statistically significant (P = 0.001). Multivariate analysis showed SRC3-pS543 to be an independent prognostic factor.Conclusions: Phosphorylation of SRC3 at S543 affects its genomic interactions on a genome-wide level, where SRC3-pS543 is selectively recruited to promoters of ERα-responsive genes. SRC3-pS543 is a prognostic marker, and a predictive marker of response to endocrine therapy. Clin Cancer Res; 22(2); 479–91. ©2015 AACR.

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