Mol. Hum. Reprod. Advance Access originally published online on July 23, 2004
Molecular Human Reproduction 2004 10(9):641-650; doi:10.1093/molehr/gah092
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Endometrial TIMP-4 mRNA is high at midcycle and in hyperplasia, but down-regulated in malignant tumours. Coordinated expression with MMP-26
Departments of 1Obstetrics & Gynaecology and 2Pathology, University Hospital, S-221 85 Lund, 3Atherosclerosis Research Unit, King Gustav V Research Institute, Karolinska Hospital, S-171 76 Stockholm, Sweden and 4Department of Obstetrics & Gynaecology, Palacky University, 775 20 Olomouc, Czech Republic
5 To whom correspondence should be addressed: Biomedical Centre C 14, Lund, S-221 84 Sweden. Email: bertil.casslen{at}gyn.lu.se
We have previously reported that endometrial expression of matrix metalloproteinase (MMP)-26 mRNA comes to a maximum in the early secretory phase. Since tissue inhibitor of metalloproteinase (TIMP)-4 is a potent inhibitor of MMP-26, the objective of this study was to identify the pattern of TIMP-4 mRNA expression in the normal endometrial cycle. We also evaluated hyperplastic, pre-malignant (atypical hyperplasia) and malignant endometrial tissue. Endometrial TIMP-4 mRNA was localized in tissue sections using in situ hybridization, and quantified in tissue extracts using real-time PCR. Estrogen receptor 
(ER) was assayed in the same set of samples using immunohistochemistry. In situ hybridization demonstrated TIMP-4 mRNA in the stroma of both normal and pathological tissues. TIMP-4 mRNA increased in the proliferative phase to a maximum in the early secretory phase, and then decreased in the late part of the cycle. Expression was comparable in normal and hyperplastic (including atypical) endometrial samples, whereas lower levels were detected in malignant tumours. Since this general pattern of expression suggests estrogen dependence, we evaluated ER in our samples. Tissue sections from the normal proliferative phase, hyperplasia and pre-malignant atypical hyperplasia tissue stained strongly for ER, whereas weak staining was seen in the secretory phase and in malignant tumours. Thus, low level of ER was accompanied by down-regulated TIMP-4 mRNA, supporting the hypothesis that ER contributes to regulation of the TIMP-4 gene. In addition, we identified a putative estrogen response element (ERE) in the promoter region of the TIMP-4 gene at position –930 to –916. Similarities in the cyclic patterns of TIMP-4 mRNA and MMP-26 mRNA, together with the fact that TIMP-4 is a potent inhibitor of MMP-26, suggest a functional relationship, and furthermore a role in human implantation.
Key words: estrogen receptor/human/implantation/pre-malignant/protease inhibitor
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