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Cyclin D2 and p27 Are Tissue-Specific Regulators of Tumorigenesis in Inhibin Knockout Mice

Department of Pathology (K.H.B., J.E.A., M.M.M.), Department of Molecular and Human Genetics (K.H.B., M.M.M.), and Department of Molecular and Cellular Biology (M.M.M.), Baylor College of Medicine, Houston, Texas 77030; and Department of Cancer Biology (P.S.), Dana-Farber Cancer Institute, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Martin M. Matzuk, M.D., Ph.D., Stuart A. Wallace Chair and Professor, Department of Pathology, One Baylor Plaza, Baylor College of Medicine, Houston, Texas 77030. E-mail: mmatzuk{at}bcm.tmc.edu.

Inhibins are heterodimeric (:ßA and :ßB) endocrine, paracrine, and autocrine factors of the TGFß superfamily that are produced predominantly by ovarian granulosa cells in females and testicular Sertoli cells in males. Control of granulosa and Sertoli cell proliferation is lost in the inhibin (Inh) knockout mouse model, leading to gonadotropin-dependent gonadal tumors of the granulosa/Sertoli cell lineage in both females and males. Castrate Inh knockout mice develop sex steroidogenic tumors of the adrenal cortex. Physiological control of granulosa/Sertoli cell cycle progression depends on p27^Kip1 and cyclin D2, which function in the G₁ S phase transition. To study the cell cycle-regulatory factors involved in ovarian, testicular, and adrenal tumor development in vivo, we have bred Inh mutant mice to mice with targeted disruptions of the p27 and cyclin D2 genes. Our previous studies demonstrated that inhibins act cooperatively with p27 to negatively regulate granulosa cell proliferation, as double mutant mice lacking inhibins and p27 develop and succumb to ovarian tumors more rapidly than Inh knockout mice. Here, we report that cyclin D2 antagonizes this inhibition and is key in promoting gonadal growth and tumor development, and tumor development is markedly suppressed in double-mutant mice. We found that double-knockout females lacking cyclin D2 and Inh lived longer than mice lacking inhibins alone; the majority of these double-knockout mice lived longer than 17 wk, as opposed to inhibin single-knockout females with 50% survival at between 12 and 13 wk of age. Moreover, 95% of inhibin knockout males succumb to testicular tumor development by 12 wk of age, whereas double knockouts were protected from early signs of tumor development and had a 50% survival of 40 wk. Interestingly, the results of these studies reflect tissue-specific consequences of loss of these cell cycle regulators. In castrate mice, loss of p27 has little effect on adrenal cortical tumor progression in the absence of inhibins, whereas loss of cyclin D2 prolongs the lifespan of cyclin D2, Inh double knockouts. After gonadectomy, 50% of cyclin D2, Inh double-knockout males live to more than 46 wk of age, 10 wk longer than 50% of littermates lacking only inhibins. Similarly, 50% of female cyclin D2, inhibin double knockouts live to 47 wk of age before succumbing to adrenal tumor development, in contrast to the 50% survival of Inh single-knockout females at between 27 and 28 wk. Thus, identification of genetic modifiers of the Inh knockout tumor phenotype has led us to a better appreciation of how specific components of the cell cycle machinery contribute to tumorigenesis in the ovary, testis, and adrenal gland.

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