Objective: In this study, we have compared the biological significance of proliferation; assessed using Ki67 labelling index (Ki67-LI), with respect to HER2 expression in oestrogen receptor positive (ER+) breast cancer to assess the impact on growth fraction and biological characteristics of luminal breast cancer. Method: 1562 well-characterised ER + breast cancers were assessed for expression of a large panel of biomarkers (no=30). Results: 53 % of the cases showed high Ki67-LI (>13 %) and 12 % showed HER2 over-expression and both were positively associated with younger age, higher tumour grade, lymph node stage and shorter outcome. Both markers were associated with up-regulation of ER-coactivators (CD71, CARM1, PI3KCA&TK1), P-cadherin, p53 and with lower levels of ER expression and down-regulation of ER-related genes (PgR, AR&GATA3) and BRCA1. Neither of the two markers was associated with expression of basal-associated cytokeratins. High Ki67-LI was associated with down-regulation of luminal enriched markers including luminal cytokeratins, MUC1, GCDFP-15, FHIT, and transcription and differentiation ERrelated genes (FOXA1 and TFF3). In contrast, HER2 expression was associated with up-regulation of luminal cytokeratins, GCDFP-15, FHIT and E-cadherin. Conclusion: Unlike high Ki67-LI, HER2 overexpression is not associated with the down-regulation of luminal enriched genes. Increased growth fraction in ER + tumours may be driven by different mechanisms in HER2+&HER2-disease.