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Invited Commentary
Gerard M Doherty, MD, FACS Boston, MA
Brown and colleagues from the Yale Endocrine Neoplasia Laboratory have made another important addition to our understanding of the molecular drivers of adrenocortical carcinoma (ACC). They have investigated the potential role of BCL9 in ACC by evaluating the expression of BCL9 transcripts and protein in ACC, benign adrenocor- tical adenomas (ACA), and normal adrenal tissue, demon- strating that more ACC samples than ACA samples have overexpression of BCL9. Finally, they evaluated the effect of BCL9 knockdown on in vitro tumor cell line growth. Ribonucleic acid sequences designed to inhibit BCL9 pro- tein expression decreased colony-forming behavior in at least 1 ACC cell line.
B-cell CLL/lymphoma 9 protein is encoded in humans by the BCL9 gene, and is a co-factor in the activation of Wnt/B-Catenin pathway activities. The Wnt/B-Catenin pathway is highly conserved across species, which accounts in part for the name “Wnt”-a portmanteau recognizing the separate description of the gene in Drosophila as “wingless” and mice as a proto-oncogene dubbed “integration 1,” or int1. Wnt/B-Catenin activity is complex, with several loci of secondary regulation of activity, and has been the subject of extensive study. In gen- eral, expression of Wnt leads to accumulation of ß-Catenin in cellular cytoplasm and subsequent translocation to the nucleus, where ß-Catenin facilitates the expression of multiple genes. Wnt acts, at least in part, by inhibiting the destruction of cytoplasmic B-Catenin via the B-Catenin destruction complex, which normally labels ß-Catenin for ubiquitination and proteasome-mediated degradation.
Over activity of the Wnt/B-Catenin pathway has been associated with many types of cancer, through a variety
of mechanisms.1 For example, the adenomatous polyposis coli (APC) protein is a key part of the ß-Catenin destruc- tion complex, and disabling mutations in the APC gene coding for that protein lead to the accumulation of ß- Catenin and development of clinical tumors, with APC acting as a mutated tumor suppressor gene. Similarly, mu- tations near the N-terminus of ß-Catenin can prevent binding of the ubiquitination complex to ß-Catenin, leading to ß-Catenin accumulation and tumor promo- tion, with ß-Catenin, in this case, acting as a mutated proto-oncogene.
Activating mutations of Wnt/ß-Catenin pathway are present in many ACC specimens and in some ACC tumor cell lines, including 1 of the 2 used in these studies. This study, however, is focused on BCL9, which appears to amplify the effect of ß-Catenin, behaving as a nuclear co-factor in the activation of ß-Catenin-mediated tran- scription. These data support a role for BCL9 overexpres- sion as a driver of some ACC tumors based on the suppression data in a single tumor cell line and overex- pression in a subset of clinical ACC specimens, including BCL9 overexpression in the nucleus, where it might be ex- pected to generate its effect. Several questions remain un- explored at this point, including the mechanism of the BCL9 overexpression in these tumors, and tumor- developmental timing of the overexpression, given that it was not exclusive to ACC. Finally, although it is tempting to hypothesize a role for targeted therapy with a BCL9 inhibitor in patients whose tumors appear to have BCL9 overexpression, we do not currently have such a targeted agent available.
The authors have noted the disappointing results from recent trials of other agents targeted to molecular changes detected in ACC. Those experiences have been disap- pointing to be sure; however, I believe that only continued work like this careful evaluation will escort us to effective agents for this difficult disease. The Yale Endocrine Neoplasia Laboratory continues to lead us all in discovering new information about these rare tumors and their work, and that of other similar clinically informed laboratories will advance us beyond the era of cytotoxic agents and mitotane for ACC treatment.
REFERENCE
1. Moor AE, Anderle P, Cantù C, et al. BCL9/9L-B-catenin signaling is associated with poor outcome in colorectal cancer. EBioMedicine 2015;2:1932-1943.