Purpose: Tamoxifen remains an important hormonal therapy for ER-positive breast cancer (BC); however, development of resistance is a major obstacle in clinics. Here, we aimed to identify novel mechanisms of tamoxifen resistance and provide actionable drug targets overcoming resistance. Experimental Design: Whole transcriptome sequencing, downstream pathway analysis and drug repositioning approaches were used to identify novel modulators (here: PDE4D) of tamoxifen resistance. Clinical data involving tamoxifen-treated ER-positive BC patients were used to assess the impact of PDE4D in tamoxifen resistance. Tamoxifen sensitization role of PDE4D was tested in vitro and in vivo. Cytobiology, biochemistry and functional genomics tools were used to elucidate the mechanisms of PDE4D-mediated tamoxifen resistance. Results: PDE4D, which hydrolyzes cAMP, was significantly overexpressed in both MCF-7 and T47D tamoxifen resistant (TamR) cells. Higher PDE4D expression predicted worse survival in tamoxifen-treated BC patients (n=469, P=0.0036 for DMFS; n=561, P= 0.0229 for RFS) and remained an independent prognostic factor for RFS in multivariate analysis (n=132, P=0.049). Inhibition of PDE4D by either siRNAs or pharmacological inhibitors (dipyridamole and Gebr-7b) restored tamoxifen sensitivity. Sensitization to tamoxifen is achieved via cAMP-mediated induction of unfolded-protein-response/ER stress pathway leading to activation of p38/JNK signaling and apoptosis. Remarkably, aspirin was predicted to be a tamoxifen sensitizer using a drug re-positioning approach and was shown to reverse resistance by targeting PDE4D/cAMP/ER stress axis. Finally, combining PDE4D inhibitors and tamoxifen suppressed tumor growth better than individual groups in vivo. Conclusions: PDE4D plays a pivotal role in acquired tamoxifen resistance via blocking cAMP/ER stress/p38-JNK signaling and apoptosis.
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