Researchers at Washington University School of Medicine in St. Louis have found that male brains have reduced levels of an important anti-cancer protein, which makes their brain cells more vulnerable to forming tumors. This new study investigated the link between brain tumors and activation of retinoblastoma protein (RB), a tumor suppressant protein which is associated with reduced cancer risk, and found that RB was significantly less active in male brain cells than in female brain cells. The exact cause for this gender based difference in activation of RB is still under investigation. The study is presented in the August issue of the Journal of Clinical Investigation.
This research explains why men are more likely to develop brain tumors than women and why the tumors are frequently more harmful in men than similar tumors in women. The most common malignant brain tumors, glioblastomas, are found to be twice as common in men and also more aggressive. Men with glioblastomas suffer greater cognitive impairments than women and do not survive as long.
"This is the first time anyone ever has identified a sex-linked difference that affects tumor risk and is intrinsic to cells, and that's very exciting," said senior author Joshua Rubin, MD, PhD, an associate professor of pediatrics, neurology and neurobiology. "These results suggest we need to go back and look at multiple pathways linked to cancer, checking for sex differences. Sex-based distinctions at the level of the cell may not only influence cancer risk but also the effectiveness of treatments."
Rubin and his team ruled out the involvement of sex hormones in these more aggressive tumors in male brain cells, as they did not correlate with age related differences in sex hormones levels in men and women.
In this study, the researchers used a cell model of glioblastoma to prove that male brain cells form tumors more readily and more quickly than female brain cells when subjected to certain genetic alterations and exposure to growth factors. The team evaluated three genes — neurofibromin, p53 and RB — that normally suppress cell division and cell survival, to see if they were naturally less active in male brain cells. These three genes are known to be mutated and disabled in many types of cancers.
Of these three genes, scientists found that RB was more likely to be inactivated in male brain cells than in female brain cells. To confirm, they disabled the RB protein in female brain cells and found that the cells were equally susceptible to becoming cancers.
The RB protein and its associated RB1 gene were implicated in cancer as early as the 1980s, and researchers have found that mutations in the RB1 gene leads to inactivation of the RB protein and formation of tumors. RB is the target of several drugs that are currently being evaluated in clinical trials, where it is hoped that the drugs will trigger the protein's anti-tumor effects and help cancer patients survive longer.
“There are other types of tumors that occur at different rates based on sex, such as some liver cancers, which occur more often in males,” Rubin said. “Knowing more about why cancer rates differ between males and females will help us understand basic mechanisms in cancer, seek more effective therapies, and perform more informative clinical trials.”