Introduction: Steroid receptor coactivator 3 (SRC3) acts as a coactivator of nuclear receptors including estrogen receptor-alpha (ER). SRC3 has been implicated in the pathogenesis of breast cancer (BC) as well as in resistance to endocrine therapy. SRC3 is phosphorylated at a number of residues following the stimulation of growth factors or hormones. Tyr24 and Ser543 are both phosphorylated upon estrogen stimulation, while Tyr24 is modulated by JNK and Ser543 by both p38 and JNK. To date, the importance and potential role of phosphorylation at these residues has not been explored in BC. In this study we assessed the protein expression of SRC3, pTyr24 and pSer543 and association with clinico-pathological features and outcome in a well defined breast cancer series.
Methods: The expressions of SRC3, pTyr24 and pSer543 were assessed in the Nottingham Tenovus Primary Breast Cancer Series which consists of 1650 cases of primary invasive. SRC3, pTyr24 and pSer543 were correlated with clinico-pathological data as well as outcome.
Results: SRC3 expression was significantly associated with unfavourable clinicopathological features including ER -ve (p = 0.02), PR –ve (p = .038), HER2 overexpression (p < 0.0001), Triple negative phenotype (p = 0.001), high proliferation (p < 0.0001), high histological grade (p < 0.001), and lympho-vascular invasion. On contrast, the expression of pSer543 was significantly associated with a luminal phenotype, well differentiation, low proliferation (low mitotic index, low Ki67 and low SPAG5; p < 0.0001), hormonal receptors (ERα+ve/PR+ve/AR+ve), absence of both ER-B1 and ER-B5 (p < 0.01), high expression of ER-α associated proteins (cyclin D1 and Bcl2; p < 0.0001), high expression of c-jun (p < 0.0001), JNK (p < 0.0001), SRC3 (p < 0.0001), T24 (p < 0.001) and active p53 transcriptional pathways that regulate cell cycle progression and apoptosis (MDM2+ve, MDM4+ve and Bax+ve; p < 0.01) and absence of basal like phenotypes (p < 0.01). The absence of pSer543 was significantly associated with loss of expression of the key DNA repair proteins including XRCC1 (p < 0.0001), BRCA1 (p < 0.0001), ATM (p = 0.008) and TOP2A (p < 0.0001) reflecting a higher risk of genomic instability. Moreover, absence of pSer543 was more common in BC with a triple negative phenotype (p < 0.001). With regard to outcome, no association with outcome based on the expression of SRC3 either with or without tamoxifen was observed. However, expression of pSer543 was associated with significantly longer disease free survival (DFS) (p < 0.00001) and breast cancer specific survival (BCSS) (p = 0.0001). Furthermore, absence of pSer543 was associated with both a shorter DFS (p = 0.007) and BCSS (p = 0.01) in ER+ ve high risk BC. pSer534 was confirmed as an independent prognostic factor after adjustment for endocrine therapy and other validated prognostic factors and absent of pSer534 was associated with a two-fold increased risk of recurrence (HR = 1.9, CI 95%= 1.2–3.1). Data on Tyr24 will also be presented.
Conclusion: Phosphorylation at Ser543 is associated with a luminal phenotype, positive prognostic factors and sensitivity to tamoxifen. Furthermore, it is an independent prognostic factor. pS543 is a novel prognostic marker in BC and warrants further investigation.
Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-22.