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Michael C. MacLeod, Ph.D.

Present Title & Affiliation

Primary Appointment

Professor, Molecular Carcinogenesis, Science Park, University of Texas MD Anderson Cancer Center, Smithville, TX

Dual/Joint/Adjunct Appointment

Adjunct Professor, College of Pharmacy, The University of Texas at Austin, Austin, TX

Research Interests

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

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/beta-catenin signaling pathway, and Wnt/beta-catenin signaling is activated in the ATF3-induced tumors. Current projects center on determining how ATF3 activates Wnt/beta-catenin signaling, whether the Wnt/beta-catenin pathway is required for ATF3-tumorigenesis, and whether ATF3 over-expression induces changes in mammary stem cell populations.

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 recently completed 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. We were able to demonstrate complete abolition of the mutagenic effects of a mustard gas analog in a murine model using lead compounds from both strategies.

Education & Training

Degree-Granting Education

1974 University of Oregon, Eugene, OR, PHD, Biology
1969 California Institute of Technology, Pasadena, CA, BS, Biology

Postgraduate Training

1975-1977 Research Associate, Biology Division, Oak Ridge National Laboratory, Oak Ridge, TN, Dr. F.T. Kenney
1974-1975 Research Associate, Department of Biology, University of Oregon, Eugene, OR, Dr. J. Postlethwait

Experience/Service

Academic Appointments

Deputy Director, Center for Research on Environmental Disease, Smithville, TX, 1/2011-3/2013
Director, Science Park, Center for Research on Environmental Disease, Smithville, TX, 1/2010-12/2010
Deputy Director, Science Park - Research Division, Center for Research on Environmental Disease, Smithville, TX, 1996-2009

Administrative Appointments/Responsibilities

Associate Director, Department of Molecular Carcinogenesis, Science Park-Research Division, University of Texas MD Anderson Cancer Center, Smithville, TX, 1997-2009

Selected Publications

Peer-Reviewed Original Research Articles

1. Abel EL, Boulware S, Fields T, McIvor E, Powell KL, DiGiovanni J, Vasquez KM, Macleod MC. Sulforaphane induces phase II detoxication enzymes in mouse skin and prevents mutagenesis induced by a mustard gas analog. Toxicol Appl Pharmacol 266(3):439-442, 2013. PMID: 23201461.
2. Boulware S, Fields T, McIvor E, Powell KL, Abel EL, Vasquez KM, MacLeod MC. 2,6-Dithiopurine, a nucleophilic scavenger, protects against mutagenesis in mouse skin treated in vivo with 2-(chloroethyl) ethyl sulfide, a mustard gas analog. Toxicol Appl Pharmacol 263(2):203-209, 2012. PMCID: PMC3422404.
3. Yan L, Coletta LD, Powell KL, Shen J, Thames H, Aldaz CM, MacLeod MC. Activation of the canonical Wnt/beta-catenin pathway in ATF3-induced mammary tumors. PLoS One 6(1):e16515, 2011. PMCID: PMC3031586.
4. Abel EL, Bubel JD, Simper MS, Powell L, McClellan SA, Andreeff M, MacLeod MC, DiGiovanni J. Protection against 2-chloroethyl ethyl sulfide (CEES) - induced cytotoxicity in human keratinocytes by an inducer of the glutathione detoxification pathway. Toxicol Appl Pharmacol 255(2):176-183, 2011. PMID: 21723306.
5. Powell KL, Boulware S, Thames H, Vasquez KM, Macleod MC. 2,6-Dithiopurine blocks toxicity and mutagenesis in human skin cells exposed to sulfur mustard analogues, 2-chloroethyl ethyl sulfide and 2-chloroethyl methyl sulfide. Chem Res Toxicol 23(3):497-503, 2010. PMCID: PMC2838951.
6. Liu J, Powell KL, Thames HD, Macleod MC. Detoxication of sulfur half-mustards by nucleophilic scavengers: Robust activity of thiopurines. Chem Res Toxicol 23(3):488-496, 2010. PMCID: PMC2838965.
7. Wang A, Arantes S, Yan L, Kiguchi K, McArthur MJ, Sahin A, Thames HD, Aldaz CM, MacLeod MC. The transcription factor ATF3 acts as an oncogene in mouse mammary tumorigenesis. BMC Cancer 8(1):268, 9/2008. PMCID: PMC2564979.

Last updated: 1/2/2014