Androgen receptor activation in HER2-negative breast cancer liver metastases.

11527 Background: The androgen receptor (AR) is expressed in the majority of breast cancers (BC) and its signaling may contribute to the development of BC metastases. The expression pattern of AR, its phosphorylated (p) form, and correlations with other BC growth and survival pathways was evaluated by protein pathway activation mapping in primary and metastatic (met) BC tissues. Methods: Group 1: 72 human BC primary and metastatic tissues underwent phosphoproteomic analysis using the TheraLink Assay, a reverse phase protein array (RPPA)-based method at a CLIA-certified laboratory (Theranostics Health). Immunostaining with 24 antibodies was directed against AR, pAR, pMet, and total and pHER1/2/3 pathway proteins. Spearman correlation was performed. Group 2: 25 met BC tissues from the SideOut Foundation-sponsored clinical trial (#NCT01919749) were analyzed by RPPA at GMU. Results: Group 1: 34 were primary BCs (55%); 38 were mets (45%). Sites of mets: liver (n = 24); lung (n = 7); chest wall (n = 7). AR expression was increased in chest wall (1.7-fold) and liver (1.3-fold) compared to primary BCs. pAR was increased in liver (2.3-fold) and chest wall (1.8-fold) compared to primary BCs. Liver mets showed a negative correlation between pAR and HER2 (p = 0.014), pAR and pHER2 (p = 0.001), and pAR and pmTOR (p = 0.046); this was observed in the 17 liver mets that were HER2–. A strong positive correlation was seen in these HER2– liver mets between total AR and pAKT (p = 0.012), pAR and p4EBP1 (p = 0.029), pAR and pMek1/2 (p = 0.006), pAR and pMet (p = 0.005), and pMet and pHER3 (p = 0.071). Group 2: Sites of mets: liver (n = 10), skin/chest wall (n = 7), lymph node (n = 3), intra-abdominal masses (n = 3), lung (n = 2). High expression levels of pAR were seen in 4/10 (40%) of the liver mets whereas 2/15 (13%) of the other mets had any measurable pAR. Conclusions: 2 independent sets of HER2 metBC tissues showed strong liver-specific activation of AR along with activation of cMet/HER3 signaling. These results suggest a possible role of AR in the growth of HER2 liver mets. Clinical trials inhibiting AR as well as HER3 or cMet kinase activity in patients with liver mets would be of interest.