Background: Current standard of care therapies with antiestrogens targeting estrogen receptor α (ER) signaling improve disease-free survival (DFS) in early-stage of breast cancer. However a significant number of cases exhibit de novo or acquired endocrine resistance and recur. It is thus important to identify novel targets of resistance and select these patients for additional therapeutic options which might include continued/extended hormonal therapy. The Oncotype Dx recurrence score (RS) in current practice predicts the likelihood of distant recurrence in tamoxifen-treated patients with node-negative, ER+ breast cancer. However, Oncotype Dx does not provide the mechanistic basis for endocrine resistance. In this study, we aimed to investigate the impact of two epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) expression on recurrence and endocrine resistance such as tamoxifen of ER+ breast cancer.

Methods: Publicly available gene expression datasets were analyzed for the overexpression of ESRP1 and ESRP2 in breast cancer. To validate the in silico findings for the ESRP1 and ESRP2 expression, we further performed quantitative real-time RT-PCR (qRT-PCR) in a cohort of 60 paraffin-embedded ER-positive node-negative breast carcinomas with low, intermediate, and high (19, 21, and 20 cases, respectively) Oncotype DX scores. To further determine the correlation between endocrine resistance and ESRP1/ESRP2 expression, we evaluated their expression levels in an established in vitro model of ER+/tamoxifen-resistance (MCF7/LCC2: an acquired tamoxifen resistant model of human breast cancer).

Results: Using publicly available breast cancer gene expression datasets, we have identified that overexpression of the epithelial splicing regulatory proteins 1 and 2 (ESRP1 and ESRP2) correlates with worse prognosis in ER+ significantly, but not in ER- breast cancers. qRT-PCR analysis further revealed that ESRP1 and ESRP2 expressions are positively correlated with high Oncotype Dx scores (P <0.05). In vitro, ESRP1 and ESRP2 levels were increased 7.48-fold (P = 0.008) and 2.98-fold (P = 0.0007) in ERα-positive cells with acquired tamoxifen resistance (MCF-7 LCC2), respectively. Thus, ESRP1 expression was slightly elevated more than ESRP2. Furthermore, both ESRP1 and ESRP2 levels did not change in response to E2 alone or E2 and tamoxifen treatment in combination.

Conclusion: These findings suggest a role for the elevated expression of ESRP1 and ESRP2 in tamoxifen resistance and recurrence of ER+ breast cancer. Further studies are ongoing to determine their mechanistic role in ER+ cancer and methods of targeting ESRP1 & 2.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P5-09-09.