Cooperative p16 and p21 action protects female astrocytes from transformation

Abstract

Mechanisms underlying sex differences in cancer incidence are not defined but likely involve dimorphism (s) in tumor suppressor function at the cellular and organismal levels. As an example, sexual dimorphism in retinoblastoma protein (Rb) activity was shown to block transformation of female, but not male, murine astrocytes in which neurofibromin and p53 function was abrogated (GBM astrocytes). Correlated sex differences in gene expression in the murine GBM astrocytes were found to be highly concordant with sex differences in gene expression in male and female GBM patients, including in the expression of components of the Rb and p53 pathways. To define the basis of this phenomenon, we examined the functions of the cyclin dependent kinase (CDK) inhibitors, p16, p21 and p27 in murine GBM astrocytes under conditions that promote Rb-dependent growth arrest. We found that upon serum deprivation or etoposide-induced DNA damage, female, but not male GBM astrocytes, respond with increased p16 and p21 activity, and cell cycle arrest. In contrast, male GBM astrocytes continue to proliferate, accumulate chromosomal aberrations, exhibit enhanced clonogenic cell activity and in vivo tumorigenesis; all manifestations of broad sex differences in cell cycle regulation and DNA repair. Differences in tumorigenesis disappeared when female GBM astrocytes are also rendered null for p16 and p21. These data elucidate mechanisms underlying sex differences in cancer incidence and demonstrate sex-specific effects of cytotoxic and targeted therapeutics. This has critical implications for lab and clinical research.Electronic supplementary materialThe online version of this article (10.1186/s40478-018-0513-5) contains supplementary material, which is available to authorized users.

Brd4-bound enhancers drive cell intrinsic sex differences in glioblastoma

“…Previously, we reported correlations between sex differences in tumorigenicity and gene expression in a murine model of GBM (11,12). Fifty percent of the sex-based differences in gene expression in the mouse model were concordantly expressed in a sex-specific fashion in human GBM patient gene expression data (11).…”

“…We have previously demonstrated transcriptome-wide differences in gene expression and clonogenic stem cell function in these male and female GBM cells (11,12) and therefore we hypothesized that these differences are endowed by sex-specific epigenetic mechanisms and more specifically sex-specific Brd4-bound enhancer activity.…”

“…Such factors may include the organizational or epigenetic effects of transient in utero sex hormones or the extra-gonadal effects of sex chromosome encoded genes. We discovered that an established model of GBM involving combined loss of neurofibromin (NF1) and p53 function in murine neocortical astrocytes exhibits sex differences in in vivo tumorigenicity (11,12) , cell cycle regulation (11,12), gene expression (11), and chemotherapy response (11) that mimic those observed in GBM patients (11,12).…”

JAM-A functions as a female microglial tumor suppressor in glioblastoma

“…Furthermore, these differences manifest clinically, with females showing a more dispersive phenotype radiographically (Yang et al, 2019) and males experiencing a poorer prognosis . There is supporting evidence in the literature suggesting that sexual dimorphism in GBM is mediated through sexspecific differences in tumor cell-intrinsic oncogenic signaling pathways (Kfoury et al, 2018;Ostrom et al, 2019;Ostrom and Kinnersley, 2018;Sun et al, 2014), epigenetic states, and metabolic profiles (Ippolito et al, 2017). While sex differences might induce differential GBM cellintrinsic responses, leading to differences in survival, sex-specific differences in the tumor microenvironment have not yet been elucidated.…”

“…The interaction between GBM cells and microglia/TAMs is principally mediated through direct cell-cell contact and a series of secreted factors, with GBM cells amplifying the immune-suppressive phenotypes of microglia/TAMs and microglia/TAMs concomitantly driving GBM cell growth and tissue infiltration (Arcuri et al, 2017;Guadagno and Presta, 2018;Sorensen and Dahlrot, 2018). An understudied barrier to effective treatment is the inherent sex differences that exist within GBM (Ippolito et al, 2017;Kfoury et al, 2018;Sun et al, 2015;Sun et al, 2014). These differences are supported at the epidemiological level, with the male to female incidence ratio being 1.6:1 (Gittleman et al, 2017;Ostrom et al, 2016;Sun et al, 2015).…”