GSTM1 gene expression correlates to leiomyoma volume regression in response to mifepristone treatment

Mikael Engman, Suby Varghese, Kristina Lagerstedt Robinson, Helena Malmgren, Anna Hammarsjö, Birgitta Byström, Parameswaran Grace L Lalitkumar, Kristina Gemzell-Danielsson, Mikael Engman, Suby Varghese, Kristina Lagerstedt Robinson, Helena Malmgren, Anna Hammarsjö, Birgitta Byström, Parameswaran Grace L Lalitkumar, Kristina Gemzell-Danielsson

Abstract

Progesterone receptor modulators, such as mifepristone are useful and well tolerated in reducing leiomyoma volume although with large individual variation. The objective of this study was to investigate the molecular basis for the observed leiomyoma volume reduction, in response to mifepristone treatment and explore a possible molecular marker for the selective usage of mifepristone in leiomyoma patients. Premenopausal women (N = 14) were treated with mifepristone 50 mg, every other day for 12 weeks prior to surgery. Women were arbitrarily sub-grouped as good (N = 4), poor (N = 4) responders to treatment or intermediate respondents (N = 3). Total RNA was extracted from leiomyoma tissue, after surgical removal of the tumour and the differential expression of genes were analysed by microarray. The results were analysed using Ingenuity Pathway Analysis software. The glutathione pathway was the most significantly altered canonical pathway in which the glutathione-s transferase mu 1 (GSTM1) gene was significantly over expressed (+8.03 folds) among the good responders compared to non responders. This was further confirmed by Real time PCR (p = 0.024). Correlation of immunoreactive scores (IRS) for GSTM1 accumulation in leiomyoma tissue was seen with base line volume change of leiomyoma R = -0.8 (p = 0.011). Furthermore the accumulation of protein GSTM1 analysed by Western Blot correlated significantly with the percentual leiomyoma volume change R = -0.82 (p = 0.004). Deletion of the GSTM1 gene in leiomyoma biopsies was found in 50% of the mifepristone treated cases, with lower presence of the GSTM1 protein. The findings support a significant role for GSTM1 in leiomyoma volume reduction induced by mifepristone and explain the observed individual variation in this response. Furthermore the finding could be useful to further explore GSTM1 as a biomarker for tailoring medical treatment of uterine leiomyomas for optimizing the response to treatment.

Clinical trials identifier: www.clinicaltrials.gov: NCT00579475, Protocol date: November 2004. https://ichgcp.net/clinical-trials-registry/NCT00579475.

Conflict of interest statement

Competing Interests: The authors have declared that no competing interests exist.

Figures

Figure 1. Flow chart explaining the patient…
Figure 1. Flow chart explaining the patient enrolment, allotment and relevent details, as per consolidated standards of reporting trials (CONSORT) in the study where leiomyoma patients were treated with mifepristone/placebo.
Figure 2. Immunohistochemical analysis of GSTM1 show…
Figure 2. Immunohistochemical analysis of GSTM1 show low immunostaining in poor responder (A) compared with good responder (B) to mifepristone treatment.
Muscle bundles (M) in good responders had higher accumaulation of GSTM1 protein than the stroma (S). Poor responders showed very low immunostaining for GSTM1 in muscle budle (M) and the smooth muscle cells of blood vessels (BV). The stroma (S) was almost negative. (Bar = 12 µ).
Figure 3. Accumulation of GSTM1 protein in…
Figure 3. Accumulation of GSTM1 protein in GR (good responders) or PR (poor responders to mifepristone treatment as demonstrated by Western Blot.
Figure 4. Correlation of leiomyoma volume change…
Figure 4. Correlation of leiomyoma volume change (percentage ×0.1) and the expression levels of GSTM1 as studied by real time PCR and Western blot GR = good responders, PR = poor responders, ND = not determined (in between groups) category.

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