Abstract
We now know that cancer is many different diseases, with great variation even within a single histological subtype. With the current emphasis on developing personalized approaches to cancer treatment, it is astonishing that we have not yet systematically incorporated the biology of sex differences into our paradigms for laboratory and clinical cancer research. While some sex differences in cancer arise through the actions of circulating sex hormones, other sex differences are independent of estrogen, testosterone, or progesterone levels. Instead, these differences are the result of sexual differentiation, a process that involves genetic and epigenetic mechanisms, in addition to acute sex hormone actions. Sexual differentiation begins with fertilization and continues beyond menopause. It affects virtually every body system, resulting in marked sex differences in such areas as growth, lifespan, metabolism, and immunity, all of which can impact on cancer progression, treatment response, and survival. These organismal level differences have correlates at the cellular level, and thus, males and females can fundamentally differ in their protections and vulnerabilities to cancer, from cellular transformation through all stages of progression, spread, and response to treatment. Our goal in this review is to cover some of the robust sex differences that exist in core cancer pathways and to make the case for inclusion of sex as a biological variable in all laboratory and clinical cancer research. We finish with a discussion of lab- and clinic-based experimental design that should be used when testing whether sex matters and the appropriate statistical models to apply in data analysis for rigorous evaluations of potential sex effects. It is our goal to facilitate the evaluation of sex differences in cancer in order to improve outcomes for all patients.
Highlights
We know that cancer is many different diseases, with great variation even within a single histological subtype
Sex differences in mitochondrial activity suggest that reactive oxygen species (ROS) accumulation, ROS regulation, and sensitivity to ROS are sexually dimorphic, as ROS is generated in the mitochondria during oxidative phosphorylation
This suggests that p53 function in the subventricular zone (SVZ) is sexually dimorphic during normal development and in response to exogenously induced DNA damage and may contribute to the sex differences in incidence and survival observed in GBM
Summary
Incidence rates were calculated by averaging age-adjusted incidence rates per 100,000 from the last 5 years (2012–2016). Sex differences in mitochondrial activity suggest that ROS accumulation, ROS regulation, and sensitivity to ROS are sexually dimorphic, as ROS is generated in the mitochondria during oxidative phosphorylation Despite their higher respiratory activity, female mouse brains accumulate significantly lower levels of ROS compared to their age-matched male counterparts [196, 197]. Co-treatment of SVZ cells in vitro with radiation and sex hormones revealed that estrogen, but not testosterone, reduced p53 expression and apoptosis in response to DNA damage [233] This suggests that p53 function in the SVZ is sexually dimorphic during normal development and in response to exogenously induced DNA damage and may contribute to the sex differences in incidence and survival observed in GBM. Given the growing body of evidence for sex differences in p53 function, p53 regulators, and tumor initiation and progression, preclinical and clinical studies focused on targeting p53 should be powered to identify sex differences in treatment response
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