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

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 β β β 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 α α 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. In both rat and mouse models, full-term pregnancy confers resistance to chemical carcinogen-induced mammary tumorigenesis (3,4) and this effect can be mimicked by treatment with estrogen, (5) estrogen and progesterone, (4) or human chorionic gonadotropin.However, the actual mechanism involved in parity protection or hormone-induced protection against breast cancer has not yet been clearly defined. The most widely accepted explanation for pregnancy protection against mammary cancer is that the pregnancy-induced differentiation of terminal end buds and terminal ducts reduces the number of target cells for carcinogenesis.It has also been reported that parous rats have decreased levels of mammogenic hormones, and this decrease has been attributed to the decreased incidence of mammary cancers in these animals. (8,9) However, complete differentiation of the mammary gland does not appear to be an obligatory prerequisite for protection against mammary carcinogenesis. (4,10,11) We have shown that pregnancy following carcinogen exposure as well as pregnancy prior to carcinogen exposure reduces mammary carcinogenesis in rats.This result indicates that pregnancy has the potential to affect the carcinogen-initiated cells that are static at the promotion phase, thus providing further support to the conclusion mentioned above.The proto-oncogene myc has long been known to stimulate cellular proliferation. Aberrant expression of Myc in the mammary glands of transgenic mice results in the development of invasive mammary adenocarcinomas. (13,14) Myc proteins are basic helix-loop-helix leucine-zipper (bHLH-Zip) transcription factors whose function relies on heterodimerization with M...

Genome Recognition by MYC

“…Moreover, MYC associates with the HATs CBP and p300 (Vervoorts et al 2003), the H3K4me3 demethylases JARID1A/KDM5A and JARID1B/ KDM5B (Secombe et al 2007), the ASH2-MLL methyl-transferase complex (Luscher-Firzlaff et al 2008), the ATPase ATAD2/ANCCA (Ciro et al 2009), and different components of the SWI/ SNF chromatin-remodeling complex (Cheng et al 1999;Park et al 2002;Pal et al 2003). Furthermore, MYC interacts with corepressor complexes containing the histone deacetylases HDAC1 (Satou 2001;Jiang et al 2007;Matsuoka et al 2008) or HDAC3 (Kurland and Tansey 2008), or the DNA methyltransferase DNMT3a (Brenner et al 2005). In addition to the commonly accepted concept that MYC, or other TFs, can recruit these cofactors to chromatin (Frank et al 2001Bouchard et al 2004), a particularly interesting scenario is that the interactions with cofactors and with the basal transcription machinery may constitute the rate-limiting steps by which MYC recognizes the restricted set of genomic regions (active or poised promoters) in which it will ultimately bind DNA.…”

MYC and Chromatin

“…Associations have been reported between MYC and two histone deacetylases (HDACs), HDAC1 [130][131][132][133] and HDAC3 [134], and in both cases MYC has been shown to recruit HDAC-containing co-repressor complexes to target loci, correlating with a reduction in histone acetylation and repression of gene activity. The relevance of this mode of transcriptional repression to the pro-tumorigenic functions of MYC is not well understood, both in terms of how histone deacetylation compares with other mechanisms of repression [135] and how repression in general contributes to the oncogenic functions of MYC [9,14,117].…”

MYC Cofactors: Molecular Switches Controlling Diverse Biological Outcomes

“…However, there is extensive evidence that MYC is directly recruited to non-E-box sequences at specific promoters through the interaction with other transcription factors, including MIZ-1, SP1/SP3, and NF-YB/NF-YC (Li et al 1994;Peukert et al 1997;Schneider et al 1997;Gartel et al 2001;Staller et al 2001). MYC interaction with these factors causes repression by recruiting HDACs (Satou et al 2001;Jiang et al 2007;Kurland and Tansey 2008;Matsuoka et al 2008).…”