Research ArticleCancer

Dosage-dependent regulation of VAV2 expression by steroidogenic factor-1 drives adrenocortical carcinoma cell invasion

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Sci. Signal.  07 Mar 2017:
Vol. 10, Issue 469, eaal2464
DOI: 10.1126/scisignal.aal2464

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Target VAV2 for adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is an aggressive cancer of the steroid hormone–producing tissue of the adrenal gland. Patients with ACC have few clinical options and poor prognosis, given that invasion and distant metastasis are often already present at the time of diagnosis. The molecular cause is unknown, but various genes exhibit increased expression in ACC tumors, including the gene encoding the transcription factor SF-1. Ruggiero et al. found that the expression of an SF-1 target gene encoding guanine exchange factor VAV2 was a critical mediator of changes in ACC cell morphology that enabled invasion in both culture and in vivo models. VAV2 is associated with progression in other tumor types, and pharmacological inhibitors against VAV2 are under development. The findings suggest that targeting VAV2 may be a future clinical option for ACC patients.

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a dismal prognosis. Genomic studies have enabled progress in our understanding of the molecular bases of ACC, but factors that influence its prognosis are lacking. Amplification of the gene encoding the transcription factor steroidogenic factor-1 (SF-1; also known as NR5A1) is one of the genetic alterations common in ACC. We identified a transcriptional regulatory mechanism involving increased abundance of VAV2, a guanine nucleotide exchange factor for small GTPases that control the cytoskeleton, driven by increased expression of the gene encoding SF-1 in ACC. Manipulating SF-1 and VAV2 abundance in cultured ACC cells revealed that VAV2 was a critical factor for SF-1–induced cytoskeletal remodeling and invasion in culture (Matrigel) and in vivo (chicken chorioallantoic membrane) models. Analysis of ACC patient cohorts indicated that greater VAV2 abundance robustly correlated with poor prognosis in ACC patients. Because VAV2 is a druggable target, our findings suggest that blocking VAV2 may be a new therapeutic approach to inhibit metastatic progression in ACC patients.

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