Investigation of glutathione S-transferase zeta and the development of sporadic breast cancer

Breast cancer is the most common malignancy in women in the Western world, with an incidence approaching one in 10 in the USA in 1980 [1] and one in 11 in Australia in 1991 [2]. Several genetic and environmental risk factors for the development of breast cancer are already known, including mutations within the BRCA1 and BRCA2 genes [3]. Other risk factors include a maternal relative with breast cancer, longer reproductive span, obesity, reproductive history and previous breast cancers [2].

Carcinogens in the body are detoxified by specific enzymes that aid in interception and removal from the cell or in modification involving addition of chemical residues to the reactive sites that cause DNA damage, allowing safe storage, prior to removal [4]. Among these enzymes are the glutathione S-transferase (GST) superfamily of enzymes, which prevent the action of electrophilic and alkylating carcinogens by binding to glutathione [5]. Several GST class enzymes have been studied to determine their role in breast cancer susceptibility. The GSTM1 null genotype has been variously reported as showing significant association in some studies [6] and no association with breast cancer [2] in other studies. The GSTT1 null genotype, however, has not been found to be involved in predisposition to sporadic breast cancer, although there is evidence that it may play a role in other cancers [2]. GSTP1 has a polymorphism resulting in an amino acid change from isoleucine to valine, which may predispose to certain cancers, including breast cancer, and has variously been found to be significant and not significant in breast cancer [2,7]. With the results from other GST classes in mind, it is possible that any new GST class discovered may have an affect on the development of several different kinds of cancer; hence the present investigation of GSTZ1.

The GSTZ1 gene has a polymorphism recently reported by Blackburn et al. [8] that is characterised by base changes from A to G at nucleotides 94 and 124 of the coding region of the gene. Hence, GSTZ1 has four alleles, GSTZ1*A (A94A124), GSTZ1*B (A94G124), GSTZ1*C (G94G124) and GSTZ1*D (G94A124), for which individuals may be homozygotic or heterozygotic. Blackburn et al. [8] reported the incidences of the alleles of GSTZ1 as 9% for GSTZ1*A, 28% for GSTZ1*B and 63% for GSTZ1*C; however, they found no incidence of GSTZ1*D at all and reported that it was non-existent, most probably due to its rarity. The base changes from A to G at nucleotides 94 and 124 lead to amino acid alterations from lysine to glutamic acid (Lys32 → Glu) and from argi-nine to glycine (Arg42 → Gly), respectively [8]. These amino acid alterations are known to affect the activities of the resultant GSTZ1 enzyme for different substrates, particularly dichloroacetates and fluroacetates, affecting the efficiency of removal for these substances. To date, the role of this gene in the development of breast cancer has not been investigated [9]. The purpose of the present study is to investigate the role of the GSTZ1 gene in the development of sporadic breast cancer.

GSTZ1 is a member of the GST superfamily of enzymes. A polymorphic variant of the gene was discovered by Blackburn et al. in 1999 [8], and the present study investigated the role of this gene variant in sporadic breast cancer. The results indicate that there is no evidence of a significant relationship between any GSTZ1 allele or allele combination and the development of sporadic breast cancer within the tested population. It is possible, however, that other factors such as exposure to certain carcinogens or lifestyle may influence this result. GSTZ1 may also interact with other detoxifying enzymes and, to accurately assess its role, analysis of these additional enzymes should be taken into account in further studies. It is also a possibility that the GSTZ1 gene is not expressed, or is only poorly expressed, in breast tissue because GST enzymes are differentially expressed in various tissues [12]. Additional studies that take other risk factors into account, as well as matching tumour types, may shed additional light on the role of GSTZ1 in sporadic breast cancer.

The results of this preliminary study indicate that the GSTZ1 gene does not appear to play a role in the development of sporadic breast cancer. This extends to both allele and genotype frequencies. The lack of association with breast cancer indicated in the present study does not, however, preclude a role in other cancers. Neither do the results invalidate further studies on GSTZ1 taking different factors such as gene expression or clinical factors (such as menopausal status) into account.