Parous mammary glands exhibit distinct alterations in gene expression and proliferation responsiveness to carcinogenic stimuli in Lewis rats.
Early full-term pregnancy affords lifetime protection against the development of breast cancer. Parity-induced protection can be reproduced in a carcinogen-induced rat mammary carcinoma model, but the molecular mechanisms of this protection against carcinogenic stimuli in rat mammary glands have not been fully characterized. To gain a better understanding of these molecular mechanisms, we used an oligonucleotide microarray to examine gene expression in parous and age-matched virgin (AMV) mammary glands of Lewis rats before and after carcinogen (N-methyl-N-nitrosourea; MNU) treatment. Parous mammary glands before MNU treatment showed up-regulation of multiple differentiation-related genes, such as whey acidic protein (Wap), casein beta (Csn2), casein gamma (Csng), lipopolysaccharide binding protein (Lbp), secreted phosphoprotein 1 (Spp1) and glycosylation-dependent cell adhesion molecule 1 (Glycam1). Also, parous mammary glands before MNU treatment exhibited down-regulation of growth-related genes such as regenerating islet-derived 3 alpha (Reg3a), mesothelin (Msln), insulin-like growth factor 2 (Igf2) and insulin-like growth factor binding protein 4 (Igfbp4). After MNU treatment, AMV mammary glands exhibited up-regulation of growth-related genes, such as Msln, cell division cycle 2 homolog A (Cdc2a), Igf2, Igfbp4, stathmin 1 (Stmn1) and homeobox, msh-like 1 (Msx1), whereas expression of these genes remained low in parous mammary glands. AMV mammary glands also exhibited marked up-regulation of Cdc2a and Stmn1 in response to MNU. After MNU treatment, the PCNA labeling index increased significantly in AMV mammary epithelial cells (13.7+/-1.1%), but remained low in parous mammary glands (3.6+/-0.4%). The response of AMV mammary glands to carcinogenic stimuli includes up-regulation of growth-related genes and increased cell proliferation. The lack of a similar response in parous mammary glands may explain parity-induced protection against mammary tumor development.
Uehara
Norihisa
N
Department of Pathology II, Kansai Medical University, Moriguchi-shi, Osaka 570-8506, Japan. ueharan@takii.kmu.ac.jp
Unami
Akira
A
Kiyozuka
Yasuhiko
Y
Shikata
Nobuaki
N
Oishi
Yuji
Y
Tsubura
Airo
A
D000818:Animals; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects*; D004847:Epithelial Cells / Q000737:chemistry / Q000166:cytology / Q000187:drug effects; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D020869:Gene Expression Profiling; D007150:Immunohistochemistry; D008321:Mammary Glands, Animal / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D000090204:Mesothelin; D008770:Methylnitrosourea / Q000633:toxicity*; D020411:Oligonucleotide Array Sequence Analysis; D000073718:Pancreatitis-Associated Proteins; D011247:Pregnancy; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D051381:Rats; D011917:Rats, Inbred Lew
D002273:Carcinogens; C000715527:MSLN protein, human; C000715529:Msln protein, rat; D000073718:Pancreatitis-Associated Proteins; D018809:Proliferating Cell Nuclear Antigen; C000612141:REG3A protein, human; D008770:Methylnitrosourea; D000090204:Mesothelin