Molecular apocrine breast cancer is an estrogen receptor negative subtype characterized by the over-expression of steroid response genes. In this study we investigate the therapeutic effects of persistent ERK phosphorylation using a Cdc25A phosphatase inhibitor, PM-20 in combination with AR inhibition using flutamide in this subtype. Our findings demonstrate a significant synergy with this combination in reducing cell viability and growth. Furthermore, we show that the mechanism of this effect involves a cross-talk between the AR and ERK signalling pathways. Moreover, using a xenograft molecular apocrine model we demonstrate that the combination therapy results in a significantly better therapeutic response compared to monotherapy and control groups manifesting as reductions in tumor growth, proliferation index, and cellularity. This study demonstrates that the combined application of AR and Cdc25A inhibitors is a promising therapeutic strategy in molecular apocrine breast cancer. © 2010 Elsevier Ireland Ltd.