Abstract
Recurrent fusion of the v-myb avian myelobastosis viral oncogene homolog (MYB) and nuclear factor I/B (NFIB) generates the MYB-NFIB transcription factor, which has been detected in a high percentage of individuals with adenoid cystic carcinoma (ACC). To understand the functional role of this fusion protein in carcinogenesis, we generated a conditional mutant transgenic mouse that expresses MYB-NFIB along with p53 mutation in tissues that give rise to ACC: mammary tissue, salivary glands, or systemically in the whole body. Expression of the oncogene in mammary tissue resulted in hyperplastic glands that developed into adenocarcinoma in 27.3% of animals. Systemic expression of the MYB-NFIB fusion caused more rapid development of this breast phenotype, but mice died due to abnormal proliferation in the glomerular compartment of the kidney, which led to development of glomerulonephritis. These findings suggest the MYB-NFIB fusion is oncogenic and treatments targeting this transcription factor may lead to therapeutic responses in ACC patients.
Highlights
Adenoid cystic carcinoma (ACC) is a malignant tumor type that arises in the salivary gland, breast, respiratory airways, and vulva [1]- [2]
At 6 weeks of age, female triallelic mice were kept in breeding cages so they could experience multiple pregnancies, as this has been shown to be required for breast carcinoma development in MMTVCre models [15]
The mammary tumor virus (MMTV)-Cre promoter has been extensively used in mouse models to drive gene expression in breast and salivary glands [15]
Summary
Adenoid cystic carcinoma (ACC) is a malignant tumor type that arises in the salivary gland, breast, respiratory airways, and vulva [1]- [2]. MYB-NFIB expression was present in 5 mammary ACCs and 6 head and neck ACCs analyzed in previous studies [4, 9, 10]. A more extensive study investigated the presence of MYB-NFIB fusion transcripts and MYB expression in more than 300 ACC tissues, including 75 salivary gland ACCs [12]. This study found fusion transcript mRNA in 28% of primary ACCs and 35% of metastatic ACCs. Further, an in-depth study of breast cancer samples using FISH and RT-PCR found the MYB-NFIB fusion gene in 12 out of 13 breast ACCs and mRNA expression in 4 out of 12 samples [5]. We investigated the role of MYB-NFIB in a novel genetically engineered mouse (GEM) model with overexpression in the salivary gland and breast compartments, either as a single genetic event or in conjunction with concurrent tumor suppressor TP53 loss
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