Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males
Tao Sun, … , Rajarshi Sengupta, Joshua B. Rubin
Tao Sun, … , Rajarshi Sengupta, Joshua B. Rubin
Published August 1, 2014
Citation Information: J Clin Invest. 2014;124(9):4123-4133. https://doi.org/10.1172/JCI71048.
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Research Article Oncology

Sexually dimorphic RB inactivation underlies mesenchymal glioblastoma prevalence in males

Abstract

The prevalence of brain tumors in males is common but unexplained. While sex differences in disease are typically mediated through acute sex hormone actions, sex-specific differences in brain tumor rates are comparable at all ages, suggesting that factors other than sex hormones underlie this discrepancy. We found that mesenchymal glioblastoma (Mes-GBM) affects more males as the result of cell-intrinsic sexual dimorphism in astrocyte transformation. We used astrocytes from neurofibromin-deficient (Nf1–/–) mice expressing a dominant-negative form of the tumor suppressor p53 (DNp53) and treated them with EGF as a Mes-GBM model. Male Mes-GBM astrocytes exhibited greater growth and colony formation compared with female Mes-GBM astrocytes. Moreover, male Mes-GBM astrocytes underwent greater tumorigenesis in vivo, regardless of recipient mouse sex. Male Mes-GBM astrocytes exhibited greater inactivation of the tumor suppressor RB, higher proliferation rates, and greater induction of a clonogenic, stem-like cell population compared with female Mes-GBM astrocytes. Furthermore, complete inactivation of RB and p53 in Mes-GBM astrocytes resulted in equivalent male and female tumorigenic transformation, indicating that intrinsic differences in RB activation are responsible for the predominance of tumorigenic transformation in male astrocytes. Together, these results indicate that cell-intrinsic sex differences in RB regulation and stem-like cell function may underlie the predominance of GBM in males.

Authors

Tao Sun, Nicole M. Warrington, Jingqin Luo, Michael D. Brooks, Sonika Dahiya, Steven C. Snyder, Rajarshi Sengupta, Joshua B. Rubin

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Figure 6

Sex differences in RB inactivation in Nf1–/– DNp53 astrocytes.

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Sex differences in RB inactivation in Nf1–/– DNp53 astrocytes. (A) Weste...
(A) Western blot analysis for RB and phospho-RB (p-RB) in protein lysates from cultures of male and female Nf1–/– DNp53 astrocytes serum starved for 48 hours (t = 0) and after addition of serum for the indicated times. Actin served as loading control. Shown are representative blots from 1 of 3 independent experiments. (B) Quantification of Western blot analysis of RB phosphorylation. Shown is the ratio of p-RB/RB as a function of time in serum (***P = 0.0001, ANOVA). (C) RB inactivation was mesured with an E2F-Luc reporter in 4 independent cultures of male and female Nf1–/– DNp53 astrocytes. For each measurement, bioluminescence was normalized to EGFP fluorescence, which was linearly related to cell number in both male and female astrocytes (inset). Male values were normalized to female values within each experiment (*P < 0.05, t test). (D) G1 fraction obtained from cell cycle analysis of male and female Nf1–/– DNp53 astrocytes cultured in serum or serum starved for 48 hours. Quantitation of 4 independent experiments is shown (*P = 0.028, t test).