The microbiota, antibiotics and breast cancer

Abstract

Breast cancer is responsible for the highest occurrence and mortality rates among the global female population, with one in eight British women diagnosed with the disease in 2019 [1]. While the 5-year survival of a patient presenting with stage 1 or 2 cancer is over 80%, patients presenting with stage 4 disease have only a 15%, 5-year survival rate [2]. Breast cancer is a heterogeneous disease classed into four major subtypes according to the presence or absence of the hormone receptors for estrogen and progesterone as well as HER2. Histological characterization of receptor status has paved the way for personalized treatments, with gene expression analysis further refining this profiling. Despite this attempt at a more ‘personalized’ treatment approach, most women receive surgery. This can either be a total mastectomy or breast conserving surgery to remove the tumor while maintaining healthy breast tissue [1,3]. For many women, this inevitably means receiving systemic antibiotic treatment before and/or after surgery. While antibiotics represent a critical treatment for bacterial infection, they do not discriminate between pathogenic and more beneficial microbes, such as those that reside in the gut, in other words, the microbiota. The gut microbiota represents a diverse and dense microbial ecosystem that plays a key role in promoting health under normal homeostatic conditions including, metabolizing dietary components in our food, infection resistance and developing and priming the immune system [4,5]. Given its key role in regulating immune processes, including both innate and adaptive responses at mucosal and system levels, it is not surprising that the gut microbiota has recently been described as playing a role in programming anticancer responses. It is increasingly clear that the composition and diversity of the gut microbiota impacts tumor immune responses [6–8], but detailed mechanistic understanding of these responses is lacking. Moreover, current cancer microbiota studies are largely focused either on cancers local to the gut or on highly immunogenic primary cancers (lung, kidney, bladder, melanoma); cancers known to respond well to immune-based therapies. Until recently, there has been little focus on microbiota and cancers that, historically, respond less favorably to immune-check point therapies, such as breast cancer. Even less analysis has been done on investigating the relation between gut microbiota and metastasis. Recently, a number of studies have started to address these gaps in our knowledge using mouse models of breast cancer [9,10]. Use of preclinical models allows for a more detailed mechanistic probing of potential underlying effects of microbiota modulation than can be performed in breast cancer patients and allows ‘targets’ to be identified that can be followed in next stage clinical studies. These studies identified that a ‘balanced’ gut microbiota is essential for programming host responses, which directly impacts tumor outcomes. As highlighted above, breast cancer patients are commonly exposed to antibiotic treatment and both studies tested the hypothesis that antibioticinduced perturbations of the gut microbiota may impact breast cancer progression. Notably, although different mouse models were used, findings indicated that antibiotic exposure significantly accelerated progression of the cancer. However, the mechanisms behind how antibiotic-induced microbiota disturbances accelerate progression