CUL4A, a Promising New Therapeutic Target for Triple Negative (Basal-Like) Breast Cancer Patients.
Sandra J Shin, Lucy Lee, Paul Chadwick, YiFang Liu, Stefano Monni, Pengbo Zhou. Weill Cornell Medical College, New York
Background: Chromosomal amplification sites tend to differ among molecular breast cancer subtypes suggesting that specific genes are critical in neoplastic development/progression (DP) in these tumors. Recently, amplification of 13q34 was reported in 20% of basal-like (BL) breast cancers. CUL4A, an ubiquitin ligase that mediates degradation of cellular proteins involved in cellular processes including cell cycle, DNA replication/repair, DNA damage checkpoint, transcription and translation is thought to be a driver in tumor DP at this locus. Triple negative breast cancers (TNBC) almost all of which are of the BL subtype have not been well-characterized for CUL4A overexpression.
Design: After confirmation of negative ER (<1%), PR (<1%) and HER-2/neu (0 or 1+) status by immunohistochemistry (IHC), TNBC specimens of 162 patients (pts) were studied. Using a tissue microarray platform, IHC staining for CUL4A (Bethyl Labortatories) and its family member CUL4B (Proteintech) was performed. IHC was assessed using the Histoscore (H score) method (range 0-300) and nuclear [N] vs cytoplasmic [C] localization was recorded. Data were statistically analysed.
Results: In 153 of 162 (94%) cases, invasive tumor cells showed N and/or C staining for either/both proteins. For CUL4A, the average H score was 84 and 10 for N and C staining, respectively while for CUL4B, it was 42 and 76. A statistically significant difference was found between N and C staining of both CUL4A and CUL4B (p<0.0001, Wilcoxon signed-rank test) N staining for CUL4A differed between invasive ductal and non-ductal histologic types, with the former having higher N CUL4A H scores (p=0.04, Wilcoxon rank-sum test [WRST]). N staining for CUL4A was higher in pts with positive nodal disease (p=0.03, WRST). No statistically significant association at the 0.05 level was found when comparing N staining for CUL4A to age, tumor size, histologic grade, lymphovascular invasion, or in-situ carcinoma. For CUL4B, C staining was associated with age (p=0.05) only and N staining did not correlate with any clinicopathologic variables studied.
Conclusions: Dysregulated CUL4A expression occurs in 94% of TNBC and although some are likely due to upregulation via the Wnt/ beta-catenin pathway, these data support the high likelihood that CUL4A is a driver in tumor DP and maintenance in many more BL breast cancers than previously thought. N staining of CUL4A significantly correlates with a subgroup of pts with positive nodal disease and/or ductal type tumors. CUL4A has the potential to be a new therapeutic target/biomarker in TNBC pts for whom treatment options are severely limited.
Monday, February 28, 2011 1:00 PM
Poster Session II # 69, Monday Afternoon