Study Demonstrates Excess of Protein Is Regulated by GATA3 in Ultra-Rare Adrenal Cancer

A new study, published in Oncotarget, delves into the mechanisms involved in a very rare cancer, adrenocortical carcinoma. For the first time, a team of researchers demonstrates the overexpression of the protein APOBEC3B while identifying the transcription factor that directly regulates it, known as GATA3.

Adrenal glands and a right-side adrenocortical carcinoma

Adrenocortical carcinoma (ACC) is a rare and aggressive cancer that forms above the kidneys in the outer layer of the adrenal gland tissue. According to the National Institutes of Health, the occurrence of ACC in the United States is believed to only affect one to two people per million, per year. This highly-rare disease also challenges patients and researchers due to its post-diagnosis five-year survival rate of a mere 51%.

At this time, there are no known external factors that cause this disease. Most adrenocortical tumors that have been found produce symptoms including abdominal pain and higher levels of certain hormones, inclusive of cortisol, aldosterone, testosterone, and estrogen. Any of these hormones produced in excess can have numerous troubling effects on the body and, most alarmingly, the cancer cells in the adrenal glands have the potential to travel to other organs.

In a recent paper published by Impact Journals’ open-access and free-to-read journal, Oncotarget, the authors began a research study to learn more about ACC and the mechanisms that lead to the biological materialization of this ultra-rare disease.

APOBEC3B In ACC

Previous to this study, recent evidence has confirmed the overexpression of a protein that is rightfully abbreviated as APOBEC3B (or Apolipoprotein B mRNA editing enzyme catalytic subunit 3B) as a source of mutations occurring in breast, bladder, cervical, lung, head, and neck cancers.

In addition to using two publicly available datasets, the researchers in this paper analyzed the APOBEC3B gene expression in 21 normal adrenal cortices, 69 benign adrenocortical tumors and 38 ACC samples. They found that APOBEC3B is also significantly overexpressed in ACC. The effects of this overexpression, in addition to a tumor, were consequently associated with DNA damage, reduced duplication (reduced number of cells in S-phase arrest), increased alterations and gene mutations (particularly in the TP53 gene).

To assess the association between APOBEC3B and adrenocortical tumor growth, the team used mouse models to perform a “knockdown,” or reduction, in APOBEC3B and measured the effects this had on the cancerous tissue. The mice were split into three groups of eight, and at weeks six and eight of the APOBEC3B knockdown, the researchers found significantly reduced cell proliferation and more cells in S-phase arrest.

The team was able to successfully knockdown APOBEC3B in mice to demonstrate that this caused a significant reduction in tumor volume. They also found in their analysis that tumors with higher expressions of APOBEC3B presented with a higher number of TP53 gene mutations.

GATA3 Binds to APOBEC3B in ACC

Given, at this point, researchers were certain that APOBEC3B is the protein that coincides with the growth of tumors in ACC, they sought to identify which mechanism is responsible for regulating this protein.

After a thorough process of tests distinguishing between 90 different cancer-associated transcription factors, the team observed that the transcription factor GATA3 directly binds to the promoter region of APOBEC3B and transcriptionally regulates its gene expression in ACC.

Conclusion

In this study, the team successfully demonstrates that in ACC, the protein APOBEC3B is overexpressed, causes tumors, and causes DNA damage, alterations, and mutations, and also, for the first time, that GATA3 directly regulates the expression of APOBEC3B. This confirms that the higher expression levels of both APOBEC3B and GATA3 are prognostic markers for patients with ACC.

This new information may be used in further research to develop treatments and interventions to improve the prognosis for those affected by adrenocortical carcinoma and other related disorders.

Oncotarget is a unique platform designed to house scientific studies in a journal format that is available for anyone to read – without a paywall making access more difficult. This means information that has the potential to benefit our societies from the inside out can be shared with friends, neighbors, colleagues and other researchers, far and wide.

Click here to read the full scientific paper, published in Oncotarget.

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