There remain to be discovered many genetic factors that influence an
individual’s risk of developing cancer. We are using p53 deficient
mice, a model of the multiple tumour syndrome Li-Fraumeni Syndrome, and
different strains of inbred mice to identify new factors involved in breast
cancer susceptibility. In collaboration with the Kathleen Cunningham
consortium for research in familial breast cancer (www.kconfab.org)
we examine the influence of these factors in breast cancer risk in human
populations. (5, 6, 12)
Dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase, is an old drug that has been used in the treatment of rare metabolic disorders that result in very high levels of lactic acid in the blood. Cancer cells are metabolically quite different to normal cells, and also produce large amounts of lactic acid. DCA has recently been shown to be able to inhibit the growth of several types of cancer cells. We are examining the ability of DCA to inhibit growth of breast cancer cells in vitro and in vivo in animal models. We are also examining the ability of DCA to work in combination with and enhance the effectiveness of other anti-cancer treatments. As DCA is a relatively non-toxic drug, we are also investigating if DCA has the ability to prevent the development of cancer in the p53 deficient mouse model, as this may offer individuals highly susceptible to breast cancer an alternative to radical preventive surgery. (1, 2)
Glutathione transferases (GSTs) are a family of drug and xenobiotic metabolising enzymes. We study the endogenous function of GSTs by looking for signs of disease in GST deficient mice. We also examine the effect of genetic variations in human GSTs on the function of GST proteins in vitro. (2-4, 7-10)
Professional Associations
- American Association for Cancer Research
- International Society for the Study of Xenobiotics
- Kathleen Cuningham Foundation Consortium for Research into Familial
breast Cancer(kConFab)
- Australian Society for Medical Research
Recent Publications
2009
1. Sun RC, Fadia M, Dahlstrom JE, Parish CR, Board PG, Blackburn AC. Reversal of the glycolytic phenotype by dichloroacetate inhibits metastatic breast cancer cell growth in vitro and in vivo. Breast Cancer Res Treat. 2009 Jun 19.
2. A. Theodoratos, W. J. Tu, J. Cappello, A. C. Blackburn, K. Matthaei and P. G. Board. Phenylalanine-induced leucopenia in genetic and dichloroacetic acid generated deficiency of glutathione transferase Zeta. Biochem Pharmacol., Accepted for publication, 2009.
2008
3. K. A. Dunphy, A. C. Blackburn, H. Yan, L. R. O’Connell, and D. J. Jerry. Estrogen and progesterone induce persistent increases in p53-dependent apoptosis and suppress mammary tumors in BALB/c-Trp53+/- mice. Breast Cancer Res., 10, R43 2008.
4. E. Schmuck, J. Cappello, M. Coggan, J. Brew, J. A. Cavanaugh, A. C. Blackburn, R. T. Baker, H. J. Eyre, G. R. Sutherland, and P. G. Board. Deletion of Glu155 causes a deficiency of glutathione transferase Omega 1-1 but does not alter sensitivity to arsenic trioxide and other cytotoxic drugs. Int J Biochem Cell Biol., 40:2553–2559, 2008.
2007
5. Blackburn AC, Hill LZ, Roberts AL, Wang J, Aud D, Jung
J, Nikolcheva T, Allard J, Peltz G, Otis CN, Cao QJ, Ricketts RS, Naber
SP, Mollenhauer J, Poustka A, Malamud D, Jerry DJ. (2007) Genetic mapping
in mice identifies DMBT1 as a candidate modifier of mammary tumors and
breast cancer risk. Am J Pathol. 170:2030-2041.
6. Koch JG, Gu X, Han Y, El-Naggar AK, Olson MV, Medina D, Jerry DJ, Blackburn
AC, Peltz G, Amos CI, Lozano G. (2007) Mammary tumor modifiers
in BALB/cJ mice heterozygous for p53. Mamm Genome. In Press.
2006
7. Blackburn AC, Matthaei KI, Lim C, Taylor MC, Cappello
JY, Hayes JD, Anders MW, Board PG. (2006)
Deficiency of glutathione transferase zeta causes oxidative stress and
activation of antioxidant response pathways. Mol Pharmacol, 69:650–657.
2005
8. Schmuck EM, Board PG, Whitbread AK, Tetlow N, Cavanaugh JA, Blackburn
AC, Masoumi A. (2005)
Characterization of the monomethylarsonate reductase and dehydroascorbate
reductase activities of Omega class glutathione transferase variants:
implications for arsenic metabolism and the age-at-onset of Alzheimer's
and Parkinson's diseases. Pharmacogenet Genomics. 15:493-501.
2004
9. Board, P.G., Anders, M.W., and Blackburn, A.C., (2004),
Catalystic Function and Expression of Glutathione Transerase Zeta. 1
ed. Drug Metabolism and Transport, eds. L.H. Lash: Humana Press Inc.
pp. 85-107.
10. Lim, C.E.L., Matthaei, K.I., Blackburn, A.C., Davis,
R.P., Dahlstrom, J.E., Koina, M.E., Anders, M.W., and Board, P.G., (2004),
Mice deficient in glutathione transferase zeta/maleylacetoacetate isomerase
exhibit a range of pathological changes and elevated expression of Alpha,
Mu, and Pi class glutathione transferases. American Journal of Pathology
165(2), 679-693.
11. Blackburn AC, McLary SC, Naeem R, Luszcz J, Stockton
DW, Donehower LA, Mohammed M, Mailhes JB, Soferr T, Naber SP, Otis CN,
Jerry DJ. (2004) Loss of heterozygosity occurs via mitotic recombination
in Trp53+/- mice and associates with mammary tumor susceptibility of
the BALB/c strain.
Cancer Res. 64:5140-7.
2003
12. Blackburn AC, Brown JS, Naber SP, Otis
CN, Wood JT, Jerry DJ (2003). BALB/c alleles for Prkdc and Cdkn2a interact
to modify tumor susceptibility in Trp53+/- mice. Cancer Res 63, 2364-8.
More Publications
2002
Blackburn AC, Jerry DJ (2002) Knockout and transgenic mice of
Trp53: what have we learned about p53 in breast cancer? Breast Cancer
Res 4, 101-11.
Jerry DJ, Minter LM, Becker KA, Blackburn AC (2002) Hormonal
control of p53 and chemoprevention. Breast Cancer Res 4, 91-4.
Smith SW and Blackburn AC. (2002) Commentary: HER-2
amplification impedes the antiproliferative effects of hormone therapy
in estrogen receptor-positive primary breast cancer. Women’s Oncol
Rev, 2:37–40.
2001
Blackburn AC, Coggan M, Tzeng H-F, Lantum H, Polekhina G, Marker
M, Anders MW and Board PG (2001) GSTZ1d, a new allele of glutathione
transferase Zeta and maleylacetoacetate isomerase. Pharmacogenetics
11, 671-678.
Board PG, Chelvanayagram G, Jermiin LS, Tetlow N, Tzeng H-F, Anders
MW and Blackburn AC (2001) Identification of novel glutathione
transferases and polymorphic variants by expressed sequence TAG database
analysis. Drug Metabolism and Disposition 29, 544-547
Polekhina G, Board PG, Blackburn AC and Parker MW (2001) The
Crystal Structure of Maleylacetoacetate Isomerase/Glutathione Transferase
Zeta reveals the Molecular Basis for its Remarkable Catalytic Promiscuity.
Biochemistry 40, 1567-1576
Taylor MC, Board PG, Mellick GD, Blackburn AC and Le Couteur
DG (2001) Zeta class glutathione transferase polymorphisms and Parkinson's
disease. Journal of Neurology, Neurosurgery and Psychiatry 70, 406-425.
Tetlow NL, Blackburn AC, Chelvanayagam G and Board PG (2001)
Alpha class glutathione transferase polymorphisms identified by EST
database analysis. Chemico-Biological Interactions 133, 123-125
2000
Blackburn AC, Tzeng H-F, Anders MW and Board PG (2000)
Discovery of a functional polymorphism in human glutathione transferase
zeta by expressed sequence tag database analysis. Pharmacogenetics 10,
49-57.
Board P, Tetlow N, Blackburn A, Chelvanayagam G (2000) Database
analysis and gene discovery in pharmacogenetics Clin Chem Lab Med 38,
863-867.
Tzeng H-F, Blackburn AC, Board PG and Anders MW (2000) Polymorphism-
and species-dependent inactivation of glutathione transferase Zeta by
dichloroacetate. Chemical Research in Toxicology 13, 231-236.
1999
Blackburn AC, Doe WF, Buffinton GD (1999) Protein carbonyl formation
on mucosal proteins in vitro and in dextran sulfate-induced colitis
Free Radical Bio Med 27: 262-270
Le Couteur DG, McLean AJ, Blackburn AC, Mellick GD and Board
PG (1999) Glutathione transferase polymorphism and Parkinson's disease.
The Lancet 353, 71-72.
1998
Blackburn AC, Woollatt E, Sutherland GR and Board PG.(1998)
Characterization and chromosome location of the gene GSTZ1 encoding
the human Zeta class glutathione transferase and maleylacetoacetate
isomerase. Cytogenetic Cell Genetics 83, 109-114.
Blackburn AC, Doe WF, Buffinton GD (1998) Salicylate
hydroxylation as an indicator of hydroxyl radical generation in dextran
sulfate-induced colitis. Free Radic Biol Med. 25:305-313
Board P, Blackburn A, Jermiin LS and Chelvanayagam
G (1998) Polymorphism of Phase II enzymes: Identification of new enzymes
and polymorphic variants by database analysis. Toxicology Letters102-103:149-154
Menegon A, Board PG, Blackburn AC, Mellick GD, LeCouteur DG
(1998) Parkinson's disease, pesticides and glutathione transferase polymorphisms.
The Lancet 352, 344-1346.
1997
Blackburn AC, Doe WF, Buffinton GD (1997) Colonic
antioxidant status in dextran sulfate-induced colitis in mice. Inflammatory
Bowel Diseases 3:198-203
