Human Microbiota and Breast Cancer—Is There Any Relevant Link?—A Literature Review and New Horizons Toward Personalised Medicine

Abstract

Breast cancer (BC) is the most common malignancy and the second cause of cancer-specific death in women from high-income countries. Recently, gut microbiota dysbiosis emerged as a key player that may directly and/or indirectly influence development, treatment, and prognosis of BC through diverse biological processes: host cell proliferation and death, immune system function, chronic inflammation, oncogenic signalling, hormonal and detoxification pathways. Gut colonisation occurs during the prenatal period and is later diversified over distinct phases throughout life. In newly diagnosed postmenopausal BC patients, an altered faecal microbiota composition has been observed compared with healthy controls. Particularly, β-glucuronidase bacteria seem to modulate the enterohepatic circulation of oestrogens and their resorption, increasing the risk of hormone-dependent BC. Moreover, active phytoestrogens, short-chain fatty acids, lithocholic acid, and cadaverine have been identified as bacterial metabolites influencing the risk and prognosis of BC. As in gut, links are also being made with local microbiota of tumoural and healthy breast tissues. In breast microbiota, different microbial signatures have been reported, with distinct patterns per stage and biological subtype. Total bacterial DNA load was lower in tumour tissue and advanced-stage BC when compared with healthy tissue and early stage BC, respectively. Hypothetically, these findings reflect local dysbiosis, potentially creating an environment that favours breast tumour carcinogenesis (oncogenic trigger), or the natural selection of microorganisms adapted to a specific microenvironment. In this review, we discuss the origin, composition, and dynamic evolution of human microbiota, the links between gut/breast microbiota and BC, and explore the potential implications of metabolomics and pharmacomicrobiomics that might impact BC development and treatment choices toward a more personalised medicine. Finally, we put in perspective the potential limitations and biases regarding the current microbiota research and provide new horizons for stronger accurate translational and clinical studies that are needed to better elucidate the complex network of interactions between host, microorganisms, and drugs in the field of BC.

How the Gut Microbiome Links to Menopause and Obesity, with Possible Implications for Endometrial Cancer Development

“…Importantly, these associations were not present in the premenopausal state, suggesting that mainly non-ovarian estrogens are responsible for these correlations. Overexpression of the microbial enzyme β-glucuronidase was associated with larger availability of systemic deconjugated estrogens [43]. Similarly, β-glucuronidase levels were inversely correlated with both deconjugated and conjugated estrogens in feces [42] and significantly correlated with urinary estrone levels, again confirming central role of estrone and the importance of these interactions in the postmenopause and contrasting the absence of these effects premenopausally [34,42].…”

“…The gut microbiome has been investigated in several female malignancies, and alterations have been seen in cervical cancer patients and after treatment in ovarian cancer patients [70][71][72]. In breast cancer, the role of the gut microbiome has been more established, with gut microbiome dysbiosis being associated with increased postmenopausal breast cancer risk and certain microbial commensals influencing breast cancer prognosis [43,73]. Moreover, one interesting study focused on PTEN mutated patients (among them 2 endometrial cancer patients), a frequently mutated gene in endometrioid endometrial cancer.…”

“…Moreover, one study examined the activity and possible relationship between the enzyme ß -glucuronidase and levels of estrogens in urine [42]. This enzyme is responsible for deconjugation of estrogens in the gut, resulting into in their reabsorption and thus a larger amount of systemic deconjugated estrogens [43]. It was found that ß-glucuronidase activity was inversely correlated with both deconjugated and conjugated estrogens in feces (p ≤ 0.01).…”

Advancements in 3D Cell Culture Systems for Personalizing Anti-Cancer Therapies

“…After centuries of research, increasing evidence implicates that microbiota influences the TME, tumor metabolism, and tumor immunotherapy response ( 48 ). For instance, gut microbiota dysbiosis may induce breast tumorigenesis ( 49 ). The influence of microbiota in tumourigenesis and tumor progression may differentially impact different types of tumors, as it has been demonstrated the existence of tumour type-specific intracellular bacteria ( 50 ).…”

“…The organ-on-chip approach could also mimic the complexity of 3D tissues or tumors, which attracts more attention to the study of microbiome and disease, an example of this approach has been applied to the gut-microbiome on a chip ( 56 , 57 ). The bidirectional interactions of drugs with local microbiota manipulate the host response to chemotherapeutic drugs ( 49 , 51 , 58 , 59 ), which potentially highlights the importance of 3D cultured models in pharmomicrobiomics. In addition, with the fast development of engineered microbial therapies, 3D cultures become a good candidate for more reliable screening, enabling parallel and long-term monitoring ( 60 ).…”