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Mnt-Deficient Mammary Glands Exhibit Impaired Involution and Tumors with Characteristics of Myc Overexpression

¹ Departments of Pediatrics and Medicine, University of California, San Diego Comprehensive Cancer Center; ² Department of Cellular and Molecular Medicine, Ludwig Cancer Institute; ³ Ludwig Cancer Institute; ⁴ Department of Family and Preventive Medicine, Division of Biostatistics and Bioinformatics; ⁵ Department of Medicine; and ⁶ Howard Hughes Medical Institute, University of California, San Diego School of Medicine, La Jolla, California; ⁷ Division of Genetic Disease Research, Graduate School of Medicine, Osaka City University, Abeno, Osaka, Japan; ⁸ Department of Cell and Developmental Biology, Shriners Hospitals for Children, Oregon Health Sciences University, Portland, Oregon; and ⁹ Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington

Requests for reprints: Anthony Wynshaw-Boris, Departments of Pediatrics and Medicine, University of California, San Diego, Medical Teaching Facility, Room 253, 9500 Gilman Drive, MC 0627, La Jolla, CA 92093-0627. Phone: 858-822-3400; Fax: 858-822-3409; E-mail: awynshawboris{at}ucsd.edu.

The proto-oncogene c-Myc plays a central role in cell growth and the development of human tumors. c-Myc interacts with Max and Myc-Max complexes bind to E-box and related sequences to activate transcription. Max also interacts with Mnt but Mnt-Max complexes repress transcription when bound to these sequences. MNT maps to human chromosome 17p13.3, a region frequently deleted in various human tumors, including mammary gland tumors. Consistent with the possibility that Mnt functions as a Myc antagonist, Mnt-deficient fibroblasts exhibit many of the hallmark characteristics of cells that overexpress Myc, and conditional (Cre/Lox) inactivation of Mnt in mammary gland epithelium leads to adenocarcinomas. Here, we further characterize mammary gland tissue following conditional deletion of Mnt in the mammary gland. We show that loss of Mnt severely disrupts mammary gland involution and leads to hyperplastic ducts associated with reduced numbers of apoptotic cells. These findings suggest that loss of Mnt in mammary tissue has similarities to Myc overexpression. We tested this directly by using promoter array analysis and mRNA expression analysis by oligonucleotide arrays. We found that Mnt and c-Myc bound to similar promoters in tumors from MMTV-c-Myc transgenic mice, and mRNA expression patterns were similar between mammary tumors from MMTV-Cre/Mnt^KO/CKO and MMTV-c-Myc transgenic mice. These results reveal an important role for Mnt in pregnancy-associated mammary gland development and suggest that mammary gland tumorigenesis in the absence of Mnt is analogous to that caused by Myc deregulation. (Cancer Res 2006; 66(11): 5565-73)

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