Background: SHON nuclear expression (SHON-Nuc + ) was previously reported to predict clinical outcomes to tamoxifen therapy in ERα + breast cancer (BC). Herein we determined if SHON expression detected by specific monoclonal antibodies could provide a more accurate prediction and serve as a biomarker for anthracycline-based combination chemotherapy (ACT). Methods: SHON expression was determined by immunohistochemistry in the Nottingham early-stage-BC cohort (n = 1,650) who, if eligible, received adjuvant tamoxifen; the Nottingham ERα − early-stage-BC (n = 697) patients who received adjuvant ACT; and the Nottingham locally advanced-BC cohort who received pre-operative ACT with/without taxanes (Neo-ACT, n = 120) and if eligible, 5-year adjuvant tamoxifen treatment. Prognostic significance of SHON and its relationship with the clinical outcome of treatments were analysed. Results: As previously reported, SHON-Nuc + in high risk/ERα + patients was significantly associated with a 48% death risk reduction after exclusive adjuvant tamoxifen treatment compared with SHON-Nuc − [HR (95% CI) = 0.52 (0.34–0.78), p = 0.002]. Meanwhile, in ERα − patients treated with adjuvant ACT, SHON cytoplasmic expression (SHON-Cyto + ) was significantly associated with a 50% death risk reduction compared with SHON-Cyto − [HR (95% CI) = 0.50 (0.34–0.73), p = 0.0003]. Moreover, in patients received Neo-ACT, SHON-Nuc − or SHON-Cyto + was associated with an increased pathological complete response (pCR) compared with SHON-Nuc + [21 vs 4%; OR (95% CI) = 5.88 (1.28–27.03), p = 0.012], or SHON-Cyto − [20.5 vs. 4.5%; OR (95% CI) = 5.43 (1.18–25.03), p = 0.017], respectively. After receiving Neo-ACT, patients with SHON-Nuc + had a significantly lower distant relapse risk compared to those with SHON-Nuc − [HR (95% CI) = 0.41 (0.19–0.87), p = 0.038], whereas SHON-Cyto + patients had a significantly higher distant relapse risk compared to SHON-Cyto − patients [HR (95% CI) = 4.63 (1.05–20.39), p = 0.043]. Furthermore, multivariate Cox regression analyses revealed that SHON-Cyto + was independently associated with a higher risk of distant relapse after Neo-ACT and 5-year tamoxifen treatment [HR (95% CI) = 5.08 (1.13–44.52), p = 0.037]. The interaction term between ERα status and SHON-Nuc + (p = 0.005), and between SHON-Nuc + and tamoxifen therapy (p = 0.007), were both statistically significant. Conclusion: SHON-Nuce + in tumours predicts response to tamoxifen in ERα + BC while SHON-Cyto + predicts response to ACT.