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Carcinogenesis Advance Access published online on April 29, 2007
Carcinogenesis, doi:10.1093/carcin/bgm100
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© The Author 2007. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Carcinogen-Induced Histone Alteration in Normal Human Mammary Epithelial Cells

Chastity Bradley*, Riet van der Meer*, Nady Roodi*, Heping Yan{dagger}, Mahesh B. Chandrasekharan§, Zu-Wen Sun§, Ray L. Mernaugh{dagger} and Fritz F. Parl*

* Department of Pathology, Vanderbilt University Medical Center, Nashville, TN 37232
{dagger} § Department of Biochemistry , Vanderbilt University Medical Center, Nashville, TN 37232

Fritz F. Parl, Vanderbilt University Medical Center, Department of Pathology, 4918 TVC, 22nd Avenue South Pierce, Nashville, TN 37232, 615-343-9117; 615-343-9563 (fax), Email: fritz.parl{at}vanderbilt.edu

Little is known about early carcinogen-induced protein alterations in mammary epithelium. Detection of early alterations would enhance our understanding of early stage carcinogenesis. Here, normal human mammary epithelial cells (HMEC) were exposed to dietary and environmental carcinogens (2-amino-1-methyl-6-phenylimidazo[4,5b]pyridine (PhIP), 4-aminobiphenyl (ABP), benzo[a]pyrene (B[a]P), 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)) individually or in combination. A phage display library of single-chain variable fragment (ScFv) antibodies was used to screen protein targets altered by the treatment. In combination with MALDI/TOF, we identified histone H3 as a target antigen. Although histone H3 total protein remained unchanged in control and treated HMEC, the methylation of lysine 4 was altered. A reduction in mono-methyl histone H3 (Lys 4) was observed in treated HMEC compared to control HMEC. This alteration was shown to be dependent on carcinogen concentration and specific for PhIP and ABP. To characterize potential histone demethylation mechanisms, localization and protein expression patterns of lysine-specific demethylase 1 (LSD1) were analyzed. In control HMEC, LSD1 was present at the nuclear periphery. However, following 72 h carcinogen treatment LSD1 localized within the nucleus. Within 48 h post-treatment, mono-methyl histone H3 (Lys 4) was restored and LSD1 localization was reversed. Protein expression levels of LSD1 were also increased in treated HMEC compared to control HMEC. Our data suggest that the induction of a single enzyme, LSD1, represents an early response to carcinogen exposure, which leads to the demethylation of histone H3 (Lys 4), which, in turn, may influence the expression of multiple genes critical in early stage mammary carcinogenesis.

Received January 17, 2007; revised April 11, 2007; accepted April 17, 2007.


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