A functionally significant cross-talk between androgen receptor and ErbB2 pathways in estrogen receptor negative breast cancer.
Recent studies have identified novel subgroups in ER-negative breast cancer based on the expression pattern of androgen receptor (AR). One subtype (molecular apocrine) has an over-expression of steroid-response genes and ErbB2. Using breast cancer cell lines with molecular apocrine features, we demonstrate a functional cross-talk between AR and ErbB2 pathways. We show that stimulation of AR and ErbB2 pathways leads to the cross-regulation of gene expression for AR, ErbB2, FOXA1, XBP1, TFF3, and KLK3. As opposed to the physiologic transient phosphorylation of extracellular signal-regulated kinase (ERK1/2) observed with the testosterone treatment, we demonstrate that the addition of ErbB2 inhibition leads to a persistent phosphorylation of ERK1/2, which negatively regulates the downstream signaling and cell growth. This suggests a mechanism for the cross-talk involving the ERK pathway. Moreover, testosterone stimulates the proliferation of molecular apocrine breast cell lines, and this effect can be reversed using antiandrogen flutamide and anti-ErbB2 AG825. Conversely, the growth stimulatory effect of heregulin can also be inhibited with flutamide, suggesting a cross-talk between the AR and ErbB2 pathways affecting cell proliferation. Importantly, there is a synergy with the combined use of flutamide and AG825 on cell proliferation and apoptosis, which indicates a therapeutic advantage in the combined blockage of AR and ErbB2 pathways.
Naderi
Ali
A
Diamantina Institute for Cancer, Immunology and Metabolic Medicine, Cancer Biology Program, University of Queensland, Princess Alexandra Hospital, Brisbane Qld 4102, Australia. a.naderi@uq.edu.au
Hughes-Davies
Luke
L
D017209:Apoptosis; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D015331:Cohort Studies; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D010766:Phosphorylation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism*; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D048049:Extracellular Signal-Regulated MAP Kinases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011944:Receptors, Androgen; D011960:Receptors, Estrogen; D013778:Tetrazolium Salts; D013844:Thiazoles; C508053:ERBB2 protein, human; C022616:thiazolyl blue