MacLeod, Michael C.

MacLeod, Michael C. Ph.D.

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Research Interests

Chemical carcinogenesis, breast cancer, DNA damage response, mustard gas

Current Research

Traditionally, my main research interests have been in understanding the initial effects of carcinogen treatment on mammalian cells and identifying cellular responses. Gene expression studies in normal human mammary epithelial cells treated with a chemical carcinogen have identified the ATF3 transcription factor gene as a ubiquitous component of these responses. ATF3 is a member of the bZip family of transcription factors, related to c-jun, but possible functions outside of the DNA damage response pathway are not well understood. We have found that overexpression of ATF3 in basal epithelial cells, driven by a keratin 5 promoter, induces hair follicle defects in transgenic mice, and results in spontaneous oral tumors in aged mice. More importantly, parous female ATF3-transgenic mice exhibit a high (~75%) incidence of mammary tumors between 6 and 12 months of age. We have also found that ATF3 is upregulated at both the mRNA and protein levels in a subset of human breast cancers. Thus, understanding the mechanism by which ATF3 acts as an oncogene in mammary tumorigenesis is the current focus of the lab. The ATF3-induced murine mammary tumors are phenotypically similar to tumors induced in recombinant models that upregulate the Wnt/b-catenin signaling pathway, and high levels of nuclear b-catenin are seen in the tumors. Current projects center on determining whether Wnt/ b-catenin signaling, and a consequent increase in mammary stem cell populations, is required for ATF3-tumorigenesis.

A second research area in my lab relates to a class of cancer chemopreventive compounds, the thiopurines. Previous work in the lab showed that 2,6-dithiopurine (DTP) protected cells and animals from the DNA-damaging effects of a variety of electrophilic carcinogens. Recent events have stimulated interest by the Department of Homeland Security and the NIH in developing protective measures against various chemical threat agents that might be used by terrorists against civilian populations. One such threat is mustard gas, bis(2-chloroethyl) sulfide. It turns out that the reactive chloroethyl groups of mustard gas follow the same electrophilic reaction pathway as the previously studied carcinogens and are therefore also subject to scavenging by DTP and other thiopurines. We are currently engaging in a collaborative, counter-terrorism effort, centered around developing both the thiopurines as direct scavengers, as well as agents that induce similar cellular defenses, as a two-pronged strategy for protecting emergency workers from the devastating effects of mustard gas.

Selected Publications

  1. Wang A, Arantes S, Conti C, McArthur M, Aldaz CM, Macleod MC. Epidermal hyperplasia and oral carcinoma in mice overexpressing the transcription factor ATF3 in basal epithelial cells, Mol Carcinog, in press, 2007
  2. Spyres L, Gaddis S, Bedford E, Arantes S, Liburd N, Powell KL, Thames H, Mitchell D, Walborg E, Rouabhia M, Aldaz CM, Macleod MC. Quantitative high-throughput measurement of gene expression with sub-zeptomole sensitivity by capillary electrophoresis, Anal Biochem, 345 (2), 284-95, 2005
  3. Thavathiru E, Ludes-Meyers JH, Macleod MC, Aldaz CM. Expression of common chromosomal fragile site genes, WWOX/FRA16D and FHIT/FRA3B is downregulated by exposure to environmental carcinogens, UV, and BPDE but not by IR, Mol Carcinog, 44 (3), 174-82, 2005
  4. Wang A, Gu J, Judson-Kremer K, Powell KL, Mistry H, Simhambhatla P, Aldaz CM, Gaddis S, MacLeod MC. Response of human mammary epithelial cells to DNA damage induced by BPDE: involvement of novel regulatory pathways, Carcinogenesis, 24 (2), 225-34, 2003
  5. Pietrasanta LI, Smith BL, MacLeod MC. A novel approach for analyzing the structure of DNA modified by Benzo[a]pyrene diol epoxide at single-molecule resolution, Chem Res Toxicol, 13 (5), 351-5, 2000

Contact Information


Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9570