BCL9 Upregulation in Adrenocortical Carcinoma: A Novel Wnt/β-Catenin Activating Event Driving Adrenocortical Malignancy
*Taylor C Brown1,2, *Norman G Nicolson1,2, *Reju Korah1,2, *Tobias Carling1,2
1Yale School of Medicine, Department of Surgery, New Haven, CT;2Yale Endocrine Neoplasia Laboratory, New Haven, CT
Objective: B-Cell CLL/Lymphoma 9 (BCL9) is a recently identified oncogene that promotes tumorigenesis via activation of the Wnt/β-Catenin signaling cascade. Though constitutively active Wnt/β-Catenin signaling is a molecular hallmark of adrenocortical carcinoma (ACC), a potential role for BCL9 to promote Wnt/β-Catenin pathway dysregulation and adrenocortical tumorigenesis, remains to be elucidated.
Design: Basic science.
Setting: Tertiary academic referral center.
Patients: Seventeen adrenocortical tumor patients (10 adrenal adenomas and 7 ACCs) who underwent adrenalectomy during 2003 to 2010.
Interventions: WNT signaling pathway PCR array analysis queried comparative expression profiles of canonical WNT pathway components including BCL9. Real-time quantitative PCR confirmed BCL9 mRNA expression levels in tumor samples. Tumor BCL9 mRNA expression levels were evaluated for correlation with tumor characteristics. RNAi gene silencing was performed in ACC cell lines SW-13 and NCI-H295R to test the potential role for BCL9 on clonal cell growth.
Main outcome measures: Tumor expression levels of BCL9; its association with tumor characteristics, and potential confirmation of its role in clonal cell growth in vitro.
Results: BCL9 gene expression levels were found to be significantly elevated in ACC compared to normal adrenal tissue (p<0.05). Furthermore, a significant correlation was observed between BCL9 mRNA levels and the malignant status of adrenocortical tumors (p<0.05). RNAi gene silencing of BCL9 inhibited clonal cell growth of SW-13 cells (p<0.05), but not NCI-H295R cells, which carry a constitutively active β-Catenin mutation.
Conclusions: BCL9 is overexpressed in malignant adrenocortical tumors and promotes clonal ACC cell growth. These findings suggest that BCL9 amplifications may serve as an alternative driver of constitutive Wnt/β-Catenin activation in ACC and could represent a potential molecular and diagnostic marker of tumor malignancy.
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