HIGH EXPRESSION OF THE POU FACTOR BRN3A IN AGGRESSIVE NEUROENDOCRINE TUMORS

A new family of POU transcription factors called Brn plays a role in d evelopment of the brain and some neuroendocrine structure. Because a m ember of this family, Brn3a, is present in the ACTH-producing mouse pi tuitary tumor AtT-20, binds to POMC promoter, and stimulates its activ ity, we studied its human homolog in ACTH-secreting or nonsecreting tu mors of pituitary and bronchial origins. A specific and quantitative r everse transcription-PCR assay was developed to assess Brn3a transcrip ts in tumor ribonucleic acid. Brn3a transcript levels were invariably low (<5 x 10(-6) arbitrary units) in four GH-, two PRL-, three gonadot ropin-, and seven of eight ACTH-producing pituitary adenomas. A single highly invasive ACTH-secreting pituitary adenoma in a patient who ult imately died with liver metastases, and the mouse corticotroph tumor c ell line AtT-20 had high Brn3a transcripts levels at 3 x 10(-5) and 4 x 10(-4) arbitrary units, respectively. Five typical bronchial carcino ids had barely detectable levels (<5 x 10(-6) arbitrary units), wherea s seven of eight small cell carcinomas of the lung (SCCLs) had extreme ly high levels (between 10(-3)-10(-1) arbitrary units); six of seven a typical bronchial carcinoids had intermediate values, between 10(-6) a nd 5 x 10(-3) arbitrary units. Although nine bronchial tumors produced POMC, there was no association between Brn3a levels and POMC gene exp ression; the two tumors with the highest POMC messenger ribonucleic ac id contents were two bronchial carcinoids with barely detectable Brn3a levels. A gel mobility shift assay was performed with a rat CRH promo ter probe that binds Brn3a; extracts of the POMC-producing human SCCL line DMS-79, which contained high levels of Brn3a transcripts, generat ed the same specific complex as did AtT-20 cell extracts. These data s how that Brn3a gene expression in neuroendocrine tumors is not correla ted with POMC gene expression; rather, it is strikingly elevated in th e highly aggressive tumors, independently of their POMC status and the ir pituitary or nonpituitary origin.