Androgen receptor (AR) activation in breast cancer (BC) liver metastases.

Abstract

11619 Background: AR is expressed in the majority of BCs and its signaling may contribute to the development of BC metastases (mets). The expression pattern of AR, its phosphorylated form, p-AR S650, and correlations with other BC growth and survival pathways were evaluated in BC mets by reverse phase protein array (RPPA). Methods: RPPA was performed on 93 FFPE primary BCs and mets at a CLIA-certified laboratory. Immunostaining with 24 antibodies was directed against AR, p-AR S650, p-MET, and total and p-HER1/2/3 pathway proteins. Clinical and genomic data were obtained from pt chart review. Analysis of variance (ANOVA) was used to assess any statistically significant differences between the groups. Results: 35 tissues were primary BCs (38%); 58 were mets (62%). Sites of mets: liver (n = 41); lung (n = 8); chest wall (n = 9). Of the 41 liver mets, 2 were triple negative (TN), 32 were ER+/HER2-, and 7 were HER2+. AR expression was increased in chest wall (1.7-fold; p = 0.038) compared to primary BCs. p-AR was increased in liver (2.0-fold; p = 0.039) and chest wall (1.8-fold; p = 0.026) compared to primary BCs. ER+ liver mets especially showed strong liver-specific activation of AR along with overexpression of HER1, HER3, VEGFR, and activation of mTOR, S6 Ribo, 4EBP1, and STAT3. MEK/ERK pathway was not activated in ER+ liver mets. HER2+ liver mets had pan-HER1/2/3 activation along with MET, SRC, S6 Ribo, 4EBP1, and JAK2/STAT3. In the 2 TN liver mets, EGFR, VEGFR, mTOR, S6 Ribo, 4EBP1, and JAK2/STAT3 were activated while AR and MEK/ERK were not. The ER+ liver mets showed higher expression of p-AR (p = 0.079), p-HER3 (p = 0.002), p-HER2 (p = 0.010) and p-Jak2 (p = 0.002) compared to primary ER+ BCs whereas the HER2+ liver mets showed lower level of p-IGFR (p = 0.049) and p-MET (p = 0.010) compared to primary HER2+ BCs. Interestingly, TN chest wall mets had higher levels of AR and p-AR (p = 0.008 and 0.044 respectively) compared to TN BCs. Conclusions: ER+ liver mets have strong expression of AR and p-AR, and all liver met subtypes showed accumulation of S6 Ribo/4EBP1 and activation of JAK2/STAT3, but not the MAPK pathway. HER1/3 and HER1/2/3 were activated in ER+ and HER2+ liver mets, respectively. These data suggest that targeting AR, HER1/3, and mTOR in ER+ liver met would be of interest.