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Accumulating evidence from clinical trials indicates that specific targeting of the IGF1 receptor (IGF1R) is not efficient as an anti-breast cancer treatment. One possible reason is that the mitogenic signals from the insulin receptor (IR) can be processed independently or as compensation to inhibition of the IGF1R. In this study, we highlight the role of the IR in mediating breast tumor progression in both WT mice and a hyperinsulinemic MKR mouse model by induction ofIr(Insr) orIgf1rknockdown (KD) in the mammary carcinoma Mvt-1 cell line. By using the specific IR antagonist-S961, we demonstrated thatIgf1r-KD induces elevated responses by the IR to IGF1. On the other hand,Ir-KD cells generated significantly smaller tumors in the mammary fat pads of both WT and MKR mice, as opposed to control cells, whereas theIgf1r-KD cells did not. The tumorigenic effects of insulin on the Mvt-1 cells were also demonstrated using microarray analysis, which indicates alteration of genes and signaling pathways involved in proliferation, the cell cycle, and apoptosis following insulin stimulation. In addition, the correlation between IR and the potential prognostic marker for aggressive breast cancer, CD24, was examined in theIr-KD cells. Fluorescence-activated cell sorting (FACS) analysis revealed more than 60% reduction in CD24 expression in theIr-KD cells when compared with the control cells. Our results also indicate that CD24-expressing cells can restore, at least in part, the tumorigenic capacity ofIr-KD cells. Taken together, our results highlight the mitogenic role of the IR in mammary tumor progression with a direct link to CD24 expression.