Prognostic Significance of Glutathione S-Transferase-Pi in Invasive Breast Cancer

Abstract

Glutathione S-transferase pi (GST-pi), a Phase II detoxification enzyme, has recently been implicated in protection against apoptosis. Expression of GST-pi and Bcl-2 protein, an established apoptosis marker, was analyzed by immunohistochemistry in 116 cases of infiltrative ductal breast carcinomas in Singapore women. The markers were correlated with apoptosis detected by the TUNEL method and clinico-pathological parameters. There were 67 (58%) GST-pi-positive breast tumors and 43 (37%) Bcl-2-positive tumors. In a large proportion of GSTpi-positive/Bcl-2-positive tumors, there was a distinct accumulation of the GST-pi enzyme within the nucleus of cancer cells when examined by double immunofluorescence labeling under confocal microscopy. GST-pi immunoreactivity was not significantly correlated with any of the traditional histologic factors known to influence prognosis, whereas Bcl-2 overexpression was associated with reduced size of primary tumor (P ‫؍‬ .021) and positive estrogen receptor status (P ‫؍‬ .001). Univariate analysis revealed that GST-pi-positive, Bcl-2-positive, and lower histological grade tumors had decreased levels of apoptosis (P ‫؍‬ .024, P ‫؍‬ .011, and P ‫؍‬ .029, respectively). However, multivariate analysis showed that histological grade and Bcl-2, but not GST-pi, immunoreactivity were correlated with apoptotic status. The Kaplan-Meier disease-free survival curves showed a significant difference between GST-pi-positive and GST-pi-negative breast cancer cases (P ‫؍‬ .002). Disease-free survival in patients with GST-pi-positive tumors was also worse than that in patients with GST-pi-negative tumors in the group who had adjuvant chemotherapy (P ‫؍‬ .04). In patients who were lymph node positive, GST-pi immunopositivity was found to influence disease-free survival. Recurrence of tumors was also significantly affected by GST-pi immunoreactivity (relative risk of 8.1). The findings indicate that GST-pipositive tumors are more aggressive and have a poorer prognosis than do corresponding GST-pinegative breast cancers.

Genetic polymorphisms in glutathione‐S‐transferase genes (GSTM1, GSTT1, GSTP1) and survival after chemotherapy for invasive breast carcinoma

“…5,6 However, this invaluable function is disadvantageous during chemotherapy, when enhanced detoxification by the glutathione/GST pathway may result in tumor resistance to cytotoxic agents. 20 Previous in vitro investigations and clinical studies have demonstrated that high levels of GST enzymes in tumors are associated with weaker responses to chemotherapy and poorer survival in patients with carcinomas of the breast, 21 stomach, 22 esophagus, 23 ovary, 24,25 and head and neck. 26 To our knowledge, only two studies on GSTP1 polymorphisms and breast carcinoma survival, conducted in the United States 14 and the United Kingdom, 15 respectively, have been reported to date.…”

Placental isoform glutathione S-transferase and P-glycoprotein expression in advanced nonsmall cell lung cancer

“…In neoplasms other than lung cancer, the overexpression of GST-pi and P-gp has been associated with decreased treatment response and survival. [16][17][18] In patients with lung cancer, the link between GST-pi and P-gp expression and tumor chemosensitivity has been documented by several trials in advanced NSCLC. 4,5,[7][8][9][10][11] In this regard, Hida et al observed that pretreatment serum GST-pi levels may be a useful parameter for predicting therapeutic response to combination chemotherapy regimens that include platinum compounds.…”

Association between GSTP1 Genotypes and Hormone Receptor Phenotype in Invasive Ductal Carcinomas of Breast

“…However, to date the results are still somewhat controversial and may vary from population to population. (Gilbert et al, 1993;Silvestrini et al, 1997;Buser et al, 1997;Helzlsouer et al, 1998;Millikan et al, 2000;Mitrunen et al, 2001;Gudmundsdottir et al, 2001;Huang et al, 2003;Egan et al, 2004;Sreenath et al, 2005;Moureau-Zabotto et al, 2006;Unlu et al, 2008;Saxena et al, 2009;Arun et al, 2010;Pongtheerat et al, 2011;Zhang et al, 2011;Ramalhinho et al, 2011;Aguiar et al, 2012;Ramalhinho et al, 2012;Saxena et al, 2013;Khabaz, 2014;Rodríguez et al, 2014).…”

“…Many previous studies revealed GSTP1 polymorphism has no correlation with clinical and pathologic tumor characteristics (Buser et al, 1997;Huang et al, 2003) only a few studies showed an inverse correlation with ER (Gilbert et al, 1993;Silvestrini et al, 1997;Moureau-Zabotto et al, 2006). Furthermore, two studies of Pongtheerat and colleagues reported that GSTP1 polymorphism was unrelated to increased risk of breast cancer, but found an inverse relationship between GSTP1 genotype and progesterone receptor protein (Pongtheerat et al, 2009;Pongtheerat et al, 2011), and positive correlation with better tumor differentiation and grade (Cairns et al, 1992;Haas et al, 2006).…”

“…Many studies investigated the possible link between GSTP1 polymorphisms and breast cancer risk, and have shown conflicting results (Gilbert et al, 1993;Silvestrini et al, 1997;Buser et al, 1997;Helzlsouer et al, 1998;Millikan et al, 2000;Mitrunen et al, 2001;Gudmundsdottir et al, 2001;Huang et al, 2003;Egan et al, 2004;Sreenath et al, 2005;Moureau-Zabotto et al, 2006;Unlu et al, 2008;Saxena et al, 2009;Arun et al, 2010;Pongtheerat et al, 2011;Zhang et al, 2011;Ramalhinho et al, 2011;Aguiar et al, 2012;Ramalhinho et al, 2012;Khabaz, 2014;Rodríguez et al, 2014). Many previous studies revealed GSTP1 polymorphism has no correlation with clinical and pathologic tumor characteristics (Buser et al, 1997;Huang et al, 2003) only a few studies showed an inverse correlation with ER (Gilbert et al, 1993;Silvestrini et al, 1997;Moureau-Zabotto et al, 2006).…”