Inhibition of androgen receptor and Cdc25A phosphatase as a combination targeted therapy in molecular apocrine breast cancer.
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.
Naderi
Ali
A
The University of Queensland Diamantina Institute, Princess Alexandra Hospital, Brisbane, Qld 4102, Australia. a.naderi@uq.edu.au
Liu
Ji
J
D000726:Androgen Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D059002:Androgen Receptor Antagonists; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D015536:Down-Regulation; D016503:Drug Delivery Systems; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D005485:Flutamide / Q000008:administration & dosage / Q000494:pharmacology*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010766:Phosphorylation; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000037:antagonists & inhibitors / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D020687:cdc25 Phosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000726:Androgen Antagonists; D059002:Androgen Receptor Antagonists; D004791:Enzyme Inhibitors; D011944:Receptors, Androgen; D005485:Flutamide; D038744:Ribosomal Protein S6 Kinases, 90-kDa; D048049:Extracellular Signal-Regulated MAP Kinases; D020687:cdc25 Phosphatases