title: GSTM1 gene expression correlates to leiomyoma volume regression in response to mifepristone treatment.
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.
  
  
  BACKGROUND
  www.clinicaltrials.gov: NCT00579475, Protocol date: November 2004. http://clinicaltrials.gov/ct2/show/NCT00579475.
authors: Department of Women's and Children's Health, Division of Obstetrics and Gynecology, Karolinska Instituet, Karolinska University Hospital, Stockholm, Sweden.
authors: Mikael
authors: M
authors: Engman
authors: Suby
authors: S
authors: Varghese
authors: Kristina
authors: K
authors: Lagerstedt Robinson
authors: Helena
authors: H
authors: Malmgren
authors: Anna
authors: A
authors: Hammarsjö
authors: Birgitta
authors: B
authors: Byström
authors: Parameswaran Grace L
authors: PG
authors: Lalitkumar
authors: Kristina
authors: K
authors: Gemzell-Danielsson
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005982:Glutathione Transferase / Q000235:genetics* / Q000378:metabolism; D006727:Hormone Antagonists / Q000627:therapeutic use*; D006801:Humans; D007889:Leiomyoma / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D015735:Mifepristone / Q000627:therapeutic use*; D020411:Oligonucleotide Array Sequence Analysis; D017697:Premenopause; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D047368:Tumor Burden / Q000187:drug effects; D014594:Uterine Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014599:Uterus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology
chemical_list: D015415:Biomarkers; D005982:Glutathione Transferase; D006727:Hormone Antagonists; D015735:Mifepristone; D011980:Receptors, Progesterone