Estradiol-dependent uterine leiomyomas in transgenic mice.

Abstract

Uterine leiomyomas are a major health problem for women of reproductive age. The molecular biology of these tumors is poorly understood partly because of the lack of relevant animal models. We have produced transgenic mice expressing the simian virus 40 T antigen driven by the promoter of

The induction of uterine leiomyomas and mammary tumors in transgenic mice expressing polyomavirus (PyV) large T (LT) antigen is associated with the ability of PyV LT antigen to form specific complexes with retinoblastoma and CUTL1 family members

“…In particular, expression of PyV LT antigen in the reproductive tracts of both males and females resulted in the development of testicular and leiomyoma tumors respectively. These observations are consistent with previous studies with transgenic mice expressing either PyV or SV40 LT antigens in the reproductive tracts (Chalifour et al, 1992;PaquisFlucklinger et al, 1993;Romagnolo et al, 1996). In both sets of transgenic strains ectopic expression of these papovaviral LT antigens resulted in the induction of either testicular or leiomyoma tumors.…”

“…In this regard, it is interesting to note that SV40 LT antigen also appears to form speci®c complexes with the CUTL1 complex (A Nepveu, personal communication). Indeed, uterine speci®c expression of SV40 LT antigen in transgenic mice also results in the induction of leiomyomas (Romagnolo et al, 1996). In addition, we have also provided evidence that the formation of these CUTL1/PyV LT complexes may be restricted to certain tissue sites.…”

“…The penetrance of the leiomyoma phenotype appeared to somewhat dependent on parity status since 50% of virgin animals developed leiomyoma (n=61) whereas only 24% of the multiparous animals were detected with leiomyoma tumors (n=23). Indeed, other groups have reported that the induction of leiomyoma in other transgenic strains may be in¯uenced by estrogen levels (Romagnolo et al, 1996).…”

“…In addition to its ability to induce mammary tumors, expression of SV40 large T in transgenic mice under transcriptional control of smooth muscle promoter has been reported to result in the induction of leiomyomas (Romagnolo et al, 1996). Whereas loss of function mutations involving the Rb gene have not been reported in sporadic leiomyomas, speci®c deletion of chromosome 7q22 has been frequently observed in human leiomyomas (Ozisik et al, 1996;Sargent et al, 1996).…”

A Mouse Model of Uterine Leiomyosarcoma

“…Loss of heterozygosity in this animal model results in the development of ULM and other reproductive tract leiomyomas in ϳ65% of the female rats (in addition to renal carcinomas), but rare ULMS are also seen. 11 Whereas transgenic mouse models of ULM also exist, [12][13][14][15] genetically modified mice developing ULMS have not been described thus far, although they could be valuable for studying the pathobiology of the tumors and for eventually providing clinically important information, especially for diagnostic purposes. In problematic STUMP cases, for example, which necessitate a detailed assessment of multiple histological variables, diagnosis and prognosis could be significantly facilitated by establishing molecular criteria.…”