Evaluation of glutathione S-transferase Pi in non-invasive ductal carcinoma of breast

Abstract

Summary Glutathione S-transferase Pi (GST P) has been reported to be a marker of dysplastic lesions. For this reason expression of GST P by intraduct breast carcinoma was evaluated by immunohistochemistry. Thirty-seven of 92 carcinomas (40%) were GST P positive. GST P staining did not correlate with histological variables, c-erbB-2 overexpression or with clinical outcome. The GST P status of recurrences did not correlate with that of the index lesion. There is little evidence that GST P is a useful marker of the potential of intraduct breast carcinoma to become invasive.The GSTs are a multigene family of intracellular proteins currently categorised into four cytosolic classes (called GST A, M, P and T) and microsomal GST (Mannervik et al., 1992). They play a major role in prevention of cell injury through catalysing detoxification reactions for a wide variety of endogenous and exogenous cytotoxins, including chemotherapeutic agents (Mannervik, 1985). The GSTs have an additional but less well-characterised function as intracellular binding proteins and may act as intracellular transport molecules for non-polar compounds, including steroid hormones (Boyer, 1989). GST P is a marker of preneoplasia in animal models of carcinogenesis (Kitahara et al., 1984), and GSTP expression is altered in early and advanced human neoplasia. It has been described as a marker for dysplastic lesions of cervix, oesophagus and colon and for intratubular germ cell neoplasia in the testis (Shiratori et al., 1987;Sato, 1989;Kodate et al., 1986;Klys et al., 1992). However, the specificity of this is in doubt since GST P expression is also increased in certain non-neoplastic epithelial proliferations, e.g. cervical viral warts (Carder et al., 1990). A wide variety of invasive carcinomas show increased GSTP expression (Howie et al., 1990), although this is not a universal phenomenon (Harrison, 1993).GST P is the major GST class in breast cancers and it is overexpressed in a subclass of oestrogen receptor-poor carcinomas (Howie et al., 1989). The implications for therapy are highlighted by data from a breast carcinoma cell line showing that increased GST expression and loss of oestrogen receptors occurs during acquisition of a multidrug-resistant phenotype (Moscow et al., 1988;Vickers et al., 1988). However the clinical value of these observations has yet to be tested. A recent immunohistochemical study of 74 cases of invasive breast carcinoma has shown heterogeneity of GST staining, but whether this is related to intrinsic drug resistance is not known (Cairns et al., 1992). The results of that study indicated that GST P expression is negatively correlated with increasing grade of carcinoma.There is, however, no published information on GST expression by intraduct breast carcinoma (ductal carcinoma in situ, DCIS), which represents the earliest morphologically recognisable form of breast carcinoma and from which invasive carcinoma may develop. The present short study aimed to analyse GST P expression by immunohistochemistry of a series of 92 p...

GSTP1 promoter hypermethylation is an early event in breast carcinogenesis

“…Loss of GSTP1 expression was observed in 49.0% of DCIS and in 17.7% of UDH. The data of GSTP1 immunohistochemistry in DCIS are consistent with previous report [3]. Promoter hypermethylation and loss of GSTP1 expression in DCIS and UDH provide opportunities for breast cancer prevention strategies including restoration of GSTP1 function via treatment with inhibition of promoter methylation.…”

Association of GSTP1 CpG Islands Hypermethylation with Poor Prognosis in Human Breast Cancers

“…It has been reported that the increased GSTP1 expression is associated with a poor prognosis [10] but conflicting results have also been reported [23]. We have also failed to demonstrate a significant association between GSTP1 expression and patient prognosis in the present study.…”

Promoter methylation and gene polymorphism are two independent events in regulation of GSTP1 gene expression

“…11 Epigenetic silencing of the GSTP1 gene mediated by promoter hypermethylation and subsequent loss of protein expression 12 has been reported in many human cancers like human neoplasia, 13 prostate cancer, 14 and breast cancer. 15 Hypermethylation of the CpG dinucleotide in the GSTP1 promoter has further been associated with aggressive phenotype 16 and poor prognosis. 17…”