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High Expression of the POU Factor Brn3a in Aggressive Neuroendocrine Tumors¹

Groupe d’Etude en Physiopathologie Endocrinienne, INSERM CJF 9208, Institut Cochin de Génétique Moléculaire, Université René Descartes, Paris, France

Address all correspondence and requests for reprints to: Dr. Yves de Keyzer, Groupe d’Etude en Physiopathologie Endocrinienne, INSERM CJF 9208, Institut Cochin de Génétique Moléculaire, 24 rue du Faubourg Saint Jacques, 74014 Paris, France.

A new family of POU transcription factors called Brn plays a role in development of the brain and some neuroendocrine structure. Because a member of this family, Brn3a, is present in the ACTH-producing mouse pituitary tumor AtT-20, binds to POMC promoter, and stimulates its activity, we studied its human homolog in ACTH-secreting or nonsecreting tumors of pituitary and bronchial origins. A specific and quantitative reverse transcription-PCR assay was developed to assess Brn3a transcripts in tumor ribonucleic acid. Brn3a transcript levels were invariably low (<5 x 10^-6 arbitrary units) in four GH-, two PRL-, three gonadotropin-, and seven of eight ACTH-producing pituitary adenomas. A single highly invasive ACTH-secreting pituitary adenoma in a patient who ultimately died with liver metastases, and the mouse corticotroph tumor cell line AtT-20 had high Brn3a transcripts levels at 3 x 10^-5 and 4 x 10^-4 arbitrary units, respectively. Five typical bronchial carcinoids had barely detectable levels (<5 x 10^-6 arbitrary units), whereas seven of eight small cell carcinomas of the lung (SCCLs) had extremely high levels (between 10^-3-10^-1 arbitrary units); six of seven atypical bronchial carcinoids had intermediate values, between 10^-6 and 5 x 10^-3 arbitrary units. Although nine bronchial tumors produced POMC, there was no association between Brn3a levels and POMC gene expression; the two tumors with the highest POMC messenger ribonucleic acid contents were two bronchial carcinoids with barely detectable Brn3a levels. A gel mobility shift assay was performed with a rat CRH promoter probe that binds Brn3a; extracts of the POMC-producing human SCCL line DMS-79, which contained high levels of Brn3a transcripts, generated the same specific complex as did AtT-20 cell extracts. These data show that Brn3a gene expression in neuroendocrine tumors is not correlated with POMC gene expression; rather, it is strikingly elevated in the highly aggressive tumors, independently of their POMC status and their pituitary or nonpituitary origin.

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