#3037 Background: Recently, a 36 kDa variant of estrogen receptor a (ER-a66), ER-a36, has been identified and cloned. ER-a36 predominantly localizes on the plasma membrane and in the cytoplasm and mediates a membrane-initiated “nongenomic” signaling pathway. In this study, we investigated the association between ER-a36 expression and tamoxifen resistance in breast cancer patients.
 Methods: ER-a36 protein expression in tumors from 710 breast cancer patients with a median follow-up of 7.9 years was assessed using immunohistochemistry (IHC) assay. Survival curves were compared using the log-rank test and multivariate analysis was performed using Cox model. All statistical tests were two-sided.
 Results: Among the patients with ER-a66 positive tumors who received tamoxifen treatment (n=307), overexpression of ER-a36 was associated with poorer disease-free survival (DFS) and disease-specific survival (DSS) and remained as an unfavorable independent factor of survival in multivariate analyses (DFS: HR=2.27; 95% CI= 1.40 to 3.68; P=. 001; DSS: HR=2.42; 95% CI= 1.37 to 4.28; P= .002). In contrast, among patients with ER-a66 positive tumors who did not receive tamoxifen (n=129), ER-a36 expression was not associated with survival, indicating a correlation between ER-a36 expression and tamoxifen resistance. Furthermore, ER-a36 expression was not associated with survival in ER-a66 negative tumors whether the patients received tamoxifen (n=73) or not (n=149). Our in vitro experiments with MCF7/ER36 cells also confirmed that high ER-a36 expression resulted in tamoxifen resistance.
 Conclusions: Patients with ER-a66 positive tumors that also express high levels of ER-a36 are less likely to benefit from tamoxifen treatment. ER-a36 is an important predictive marker for tamoxifen therapy in ER-a66 positive breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3037.

Keratins (KRTs), the intermediate filament-forming proteins of epithelial cells, are extensively used as diagnostic biomarkers in cancers and associated with tumorigenesis and metastasis in multiple cancers. However, the diverse expression patterns and prognostic values of KRTs in melanoma have yet to be elucidated. In the current study, we examined the transcriptional and clinical data of KRTs in patients with melanoma from GEO, TCGA, ONCOMINE, GEPIA, cBioPortal, TIMER and TISIDB databases. We found that the mRNA levels of KRT1/2/5/6/8/10/14/15/16/17 were significantly differential expressed between primary melanoma and metastatic melanoma. The expression levels of KRT1/2/5/6/10/14/15/16/17 were correlated with advanced tumor stage. Survival analysis revealed that the high transcription levels of KRT1/5/6/14/15/16/17 were associated with low overall survival in melanoma patients. GSEA analysis indicated that the most involved hallmarks pathways were P53 pathway, KRAS signaling, estrogen response early and estrogen response late. Furthermore, we found some correlations among the expression of KRTs and the infiltration of immune cells. Our study may provide novel insights for the selection of prognostic biomarkers for melanoma.