Sex differences in cancer mechanisms

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.

Androgen and Androgen Receptors as Regulators of Monocyte and Macrophage Biology in the Healthy and Diseased Lung

“…Furthermore, men and women develop different specific types of lung cancer. Malignant mesothelioma is more common in men, while women develop more adenocarcinoma ( 87 ), particularly non-small cell lung cancer (NSCLC) ( 88 ). Women have a superior survival rate for lung cancer compared to men ( 89 ).…”

The prognostic value of gender in gastric gastrointestinal stromal tumors: a propensity score matching analysis

“…Studies have found that sex hormones and their metabolites are involved in the development of many tumors, such as colorectal cancer, prostate cancer, breast cancer, and lung cancer [ 18 – 21 ]. The sex hormone signaling pathway may affect cancer susceptibility and the tumor microenvironment through a variety of mechanisms [ 22 ]. For example, fat-soluble steroid hormones act on intracellular receptors, causing their receptors to shuttle through the nucleus, affecting DNA methylation and chromatin conformation [ 23 ].…”

Preventative Effect of Mebendazole against Malignancies in Neurofibromatosis 1

“…Notably, the male bias of NPcis mice in developing MPNST has been reported before [ 27 ]. One could also envision intrinsic factors such as the tumor microenvironment, inflammation and differences in the sex hormones as potential causes of this phenomenon [ 26 , 28 , 29 ]; however, the underlying mechanism is unclear and should be investigated further in animals and humans. Our data further suggest that MBZ′s cytotoxic effect on NF1-related malignancies may result from a reduction in activated GTP-bound Ras and a subsequent decrease in pERK in MBZ-treated malignancies in vivo, thus directly targeting the molecular underpinnings for tumor development in this condition.…”