MEN1 gene replacement therapy reduces proliferation rates in a mouse model of pituitary adenomas.
Multiple endocrine neoplasia type 1 (MEN1) is characterized by the combined occurrence of pituitary, pancreatic, and parathyroid tumors showing loss of heterozygosity in the putative tumor suppressor gene MEN1. This gene encodes the protein menin, the overexpression of which inhibits cell proliferation in vitro. In this study, we conducted a preclinical evaluation of MEN1 gene therapy in pituitary tumors of Men1(+/-) mice, using a recombinant nonreplicating adenoviral serotype 5 vector that contained the murine Men1 cDNA under control of a cytomegalovirus promoter (Men1.rAd5). Pituitary tumors in 55 Men1(+/-) female mice received a transauricular intratumoral injection of Men1.rAd5 or control treatments, followed by 5-bromo-2-deoxyuridine (BrdUrd) in drinking water for four weeks before magnetic resonance imaging (MRI) and immunohistochemical analysis. Immediate procedure-related and 4-week mortalities were similar in all groups, indicating that the adenoviral gene therapy was not associated with a higher mortality. Menin expression was higher in the Men1.rAd5-treated mice when compared with other groups. Daily proliferation rates assessed by BrdUrd incorporation were reduced significantly in Men1.rAd5-injected tumors relative to control-treated tumors. In contrast, apoptotic rates, immune T-cell response, and tumor volumes remained similar in all groups. Our findings establish that MEN1 gene replacement therapy can generate menin expression in pituitary tumors, and significantly reduce tumor cell proliferation.
Academic Endocrine Unit, Nuffield Department of Clinical Medicine, Oxford Centre for Diabetes, Endocrinology and Metabolism, Churchill Hospital, Headington, Oxford, United Kingdom.
Gerard V
GV
Walls
Manuel C
MC
Lemos
Mahsa
M
Javid
Miriam
M
Bazan-Peregrino
Jeshmi
J
Jeyabalan
Anita A C
AA
Reed
Brian
B
Harding
Damian J
DJ
Tyler
Daniel J
DJ
Stuckey
Sian
S
Piret
Paul T
PT
Christie
Olaf
O
Ansorge
Kieran
K
Clarke
Len
L
Seymour
Rajesh V
RV
Thakker
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D049109:Cell Proliferation; D004195:Disease Models, Animal; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D057809:HEK293 Cells; D006801:Humans; D007150:Immunohistochemistry; D008279:Magnetic Resonance Imaging; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010902:Pituitary Gland / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy*; D011518:Proto-Oncogene Proteins / Q000235:genetics* / Q000378:metabolism; D011859:Radiography
C484898:Men1 protein, mouse; D011518:Proto-Oncogene Proteins