Induction of a novel histone deacetylase 1/c-Myc/Mnt/Max complex formation is implicated in parity-induced refractoriness to mammary carcinogenesis

Yoichiro Matsuoka, Katsumi Fukamachi, Norihisa Uehara, Hiroyuki Tsuda, Airo Tsubura

Research output: Contribution to journalArticlepeer-review

12 Citations (Scopus)

Abstract

Refractoriness to carcinogen-induced increases in epithelial cell proliferation is a very important characteristic of parous mammary glands. We found that N-methyl-N-nitrosourea (MNU)-induced proliferative burst in the mammary ductal epithelium was blocked in parous glands but not in age-matched virgin (AMV) glands. The inhibition of the proliferative burst in MNU-treated parous mammary glands coincided with the upregulation of Mnt, a Myc-suppressor, and the formation of histone deacetylase 1/Mnt/Max complexes that unexpectedly contained c-Myc. These complexes formed on the promoters of Myc targets, such as ornithine decarboxylase, cyclin D2, and transforming growth factor β1 genes, in quiescent fibroblasts, and were disassembled in serum-stimulated cells. These results suggest that the complexes also function as transcription repressors of the growth-related Myc targets in MNU-treated parous mammary glands. Using the chemical mammary carcinogenesis model of human c-Ha-ras transgenic (Tg) rats, we confirmed that parity protected the mammary glands at the postinitiation phase of tumorigenesis. Although the incidence of 7,12-dimethylbenz[α]anthracene-induced palpable tumors was reduced from 61.5% in the AMV Tg rats to 28.5% in the parous animals, the incidence of early neoplastic lesions in the parous rats was the same as that in the AMV rats. Restriction fragment length polymorphism analysis detected mutations in the human c-Ha-ras gene in most of the normal-appearing parous Tg glands, as well as in the virgin glands. We propose that accelerated formation of HDAC1/c-Myc/Mnt/Max complexes in response to carcinogen exposure results in down-regulation of growth-related genes, leading to the refractoriness of parous mammary glands at the postinitiation phase of carcinogenesis.

Original languageEnglish
Pages (from-to)309-315
Number of pages7
JournalCancer Science
Volume99
Issue number2
DOIs
Publication statusPublished - Feb 2008
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Induction of a novel histone deacetylase 1/c-Myc/Mnt/Max complex formation is implicated in parity-induced refractoriness to mammary carcinogenesis'. Together they form a unique fingerprint.

Cite this