A pilot study of pi-class glutathione S-transferase expression in breast cancer: correlation with estrogen receptor expression and prognosis in node-negative breast cancer.

Summary Identification and quantitative evaluation of drug resistance markers are essential to assess the impact of multidrug resistance (MDR) in clinical oncology. The MDR1 gene confers pleiotropic drug resistance in tumour cells, but other molecular mechanisms are also involved in drug resistance. In particular, the clinical pattern of expression of the other MDR-related genes is unclear and their interrelationships are still unknown. Here, we report standardization of the procedures used to determine a reliable method of semiquantitative reverse transcriptase polymerase chain reaction (RT-PCR) using a standard series of drug-sensitive and increasingly resistant cell lines to evaluate the expression of three MDR-related genes, i.e. MDR1 (multidrug resistance gene 1), MRP (multidrug resistance related protein) and GSTp (glutathione-S-transferase p), reported to be endogenous standard genes for normalization of mRNAs. A total of 74 breast cancer surgical biopsies, obtained before any treatment, were evaluated by this method. When compared with classical clinical and laboratory findings, GSTp mRNA level was higher in diploid tumours. However, the main finding of our study suggests a clear relationship between two of these MDR-related gene expressions, namely GSTp and MRP. This finding provides new insight into human breast tumours, which may possibly be linked to the glutathione conjugate carrier function of MRP. Well defined semiquantitative RT-PCR procedures can therefore constitute a powerful tool to investigate MDR phenotype at mRNA levels of different related genes in small and precious tumour biopsy specimens.

Section: Discussioncontrasting

confidence: 95%

Section: Discussionmentioning

confidence: 99%

Comparative evaluation by semiquantitative reverse transcriptase polymerase chain reaction of MDR1, MRP and GSTp gene expression in breast carcinomas

Lacave

Coulet²,

Ricci³

et al. 1998

“…The value of GST isoenzymes as markers of disease outcome have been investigated in other malignancies. In node-negative breast cancer increased GST acidic isoenzyme measured immunohistochemically was associated with decreased disease-free survival and overall survival (Gilbert et al, 1993), but there was no correlation between the level of GST isoenzyme expression and the length of disease-free survival in nodepositive breast cancer when the isoenzymes were quantified by Western blot (Peters et al, 1993). In gastric cancer an immunohistochemical study showed no significant correlation between GST acidic isoenzyme expression and clinicopathological features or prognosis (Okuyama et al, 1994), but in oral cancer the acidic isoenzyme was considered to be a useful aid to early diagnosis, prediction of disease extent and outcome (Hirata et al, 1992).…”

Section: Discussionmentioning

confidence: 95%

“…The glutathione transferase enzymes are a group of cytosolic proteins capable of catalysing detoxification pathways involved in the breakdown of a number of chemotherapeutic agents (Mannervik and Danielson, 1988). Certain of the isoenzymes have been implicated as markers of early disease recurrence in nodenegative breast cancer (i isoenzyme) (Gilbert et al, 1993), squamous cell oral cancer (x isoenzyme) (Hirata et al, 1992), childhood acute lymphoblastic leukaemia (y isoenzyme) (Hall et al, 1994) and acute non-lymphoblastic leukaemia (7x isoenzyme) (Tidefelt et al, 1992).…”

mentioning

confidence: 99%

Glutathione-S-transferase activity and isoenzyme levels measured by two methods in ovarian cancer, and their value as markers of disease outcome

Wrigley

McGown²,

Buckley³

et al. 1996

Summary A study has been carried out to investigate the cellular distribution and levels of glutathione-Stransferase isoenzymes (GST), acidic (7t), basic (x) and neutral (p), in ovarian tumour biopsies, and to measure GST activity in the same tumour specimens. Two methods of assessing isoenzyme levels (immunohistochemistry and Western blot) were compared. Well-known important clinicopathological features were correlated with response to treatment, overall survival and progression-free survival for each of 97 patients from whom biopsies had been obtained. The glutathione-S-transferase isoenzyme levels were also correlated with overall and progression-free survival, and with the important clinicopathological features. As expected, there was a significant correlation between FIGO stage, histological grade of tumour, amount of residual disease after staging laparotomy, response to chemotherapy, and both overall and progression-free survival. Glutathione-Stransferase isoenzyme levels (acidic, basic and neutral) measured by Western blot were not found to be significantly correlated with any of the clinicopathalogical parameters tested. Using the immunohistochemistry method of detection there was a correlation between the GST acidic isoenzyme level and the amount of residual disease remaining after initial debulking surgery (higher levels were detected in the group with no residual disease, P=0.034), and also between the GST acidic isoenzyme level and the type of chemotherapy regimen used. Higher levels of the acidic isoenzyme were present in tumour biopsies taken from the patient group who had received a combination regimen (cyclophosphamide, carboplatin, ifosfamide and doxorubicin). The neutral and basic GST isoenzyme levels were not significantly correlated with any of the clinicopathalogical parameters. None of the GST isoenzyme levels were significantly correlated with response to treatment, overall survival or progression-free survival (using either method of detection). Similarly, glutathione transferase activity showed no significant correlation with prognosis or survival.

“…A significant increase in GSTi expression was observed following tamoxifen treatment. GSTx gene is highly expressed in ER-negative breast cancer cell lines (Morrow et al, 1992) and tumours (Howie et al, 1989;Moscow et al, 1988;Gilbert et al, 1993). Comparing ER-and ER' cell lines, Morrow et al (1992) showed that endogenous GSTi gene transcription rates are similar in both cell lines but the stability of endogeneous GSTi mRNA is extraordinarily higher in ER-negative cells.…”

Section: Discussionmentioning

confidence: 99%

Variation of hormonal receptor, pS2, c-erbB-2 and GSTπ contents in breast carcinomas under tamoxifen: a study of 74 cases

Soubeyran

Quénel²,

Mauriac³

et al. 1996

Summary Seventy-four post-menopausal patients with primary non-metastatic invasive ductal carcinomas of the breast were first treated with tamoxifen alone (30 mg p.o. daily) for 5 months. To study changes induced by tamoxifen, core biopsies before treatment and surgical specimens after hormonal therapy were assayed by immunohistochemistry for oestrogen (ER) and progesterone receptors (PR), pS2, GSTh and c-erbB-2. After tamoxifen, ER and PR significantly decreased in 60 and 44 cases respectively, whereas 11 and 19 cases showed no variation and 2 and II cases showed an increase (P< 10-4). GSTir and pS2 showed a significant increase in 43 and 41 cases, a decrease in 2 and 21 cases and no variation in 29 and 12 cases (P<.10-4 and P=0.04 respectively). c-erbB-2 showed no significant variation under tamoxifen, increased in only three cases and decreased in 13 cases. No relation was found between these variations and efficiency of hormone therapy. Our results allow a better knowledge of protein expression modifications occurring in breast cancer cells under tamoxifen therapy. They are also more consistent with clone selection rather than with phenotype modification.