Breast cancer will affect 1 in 8 women in their lifetime. We are currently aware of multiple risk factors such as genetics, diet, and age.
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Despite this, the aetiology of most breast cancers remains unknown. The microbiome is the collection of microbes that inhabit the human body, allowing a delicate and symbiotic balance. If this balance is lost (dysbiosis), it can lead to pathologies such as obesity and colon cancer.
It has been estimated that the human gut contains 1000 bacterial species which can express 100-fold more genes than the human genome. Therefore, it is possible to suggest that this delicate relationship has the potential to drive tumour progression.
Thus, the focus here will be on the delicate host-microbiome relationship, including the GI bacterial ability to modulate bacteria in distal sites to drive breast tumorigenesis. The potential role of probiotics in treatment will then be examined.
The microbiome in cancer development
Previous work has identified the role of dysbiosis in disease development, particularly in colorectal cancer (CRC) where it was identified through an increased expression in the Fusobacterium sp., which could have pro-inflammatory properties, supporting cancer growth in tissues.
It is possible to suggest that interplay could be applied to other tissues, as the bacteria may exert effects on its host in several ways (Figure 1).
figure 1: A simple diagram exploring the proposed relationship between bacterial dysbiosis and the progression of cancer. Microbe-associated molecular patterns (MAMPs) can bind to TLRs and NLRs, inducing the upregulation of pro-inflammatory cytokines. This leads to the promotion of cellular proliferation and inhibition of apoptosis, which are two of the key hallmarks in neoplastic development.
Tumour-associated inflammation is a prominent hallmark in the field of cancer biology. Understanding of the mechanisms of tumour-associated inflammation will offer novel treatment targets.
The enzyme cyclo-oxygenase-2 (COX-2) is overexpressed in breast cancer. COX-2 overexpression is associated with an increase in prostaglandin-E2 (PGE-2), which contributes to a pro-inflammatory environment. COX-2 inhibitors are more widely known as non-steroidal anti-inflammatories (NSAIDs). The use of NSAIDs has been associated with a reduction in both the incidence and invasive potential of breast cancers.
The prolonged immune activation following a bacterial infection accounts for an elevated level of COX-2 and PGE-2 which, if sustained, leads to the early stages of tumorigenesis.
This sustained inflammatory response will modulate immune cells such as neutrophils to drive the metastatic potential of the primary breast tumour.
Neutrophils have the ability, once recruited to the breast tumour, to modulate key mechanisms in the metastatic cascade through the generation of reactive oxygen species, inducing further DNA damage and inflammation.
This leads to the upregulation of matrix-degrading enzymes such as MMP-9, which has been validated in the MDA-MB-231 breast cancer cell line where neutrophils aid in movement across a monolayer of endothelial cells in vivo.
Activated neutrophils release proteinases into the surrounding tissue, leading to damage to the host tissues.
The breast microbiome in cancer
GI Bacteria are becoming increasingly important due to their ability to modulate distal bacteria in order to exert an effect on other tissues such as breast. The microbiome of normal and malignant breast tissues are significantly different. Whilst this may account for risk factors such as breastfeeding, it is not known if this is a cause or consequence of tumorigenesis.
Each body site has its own distinct microbiome, suggesting specificity of microbial and inflammatory effects. 16S rDNA studies of breastfeeding women have identified a diverse range of bacterial communities which differs from that of normal tissue.
The microbiota of the normal breast tissue adjacent to invasive cancer was notably different from that of normal breast tissue adjacent to benign disease.
An overview of taxonomic profiles found that the overall microbiota of breast tissue between the two disease conditions seems similar, dominated by Firmicutes and Bacteroidetes. Bacterial imbalances within breast cancer patients have been attributed to a high fat diet (a known risk factor) and its intricate metabolomic relationship.
Previous work reported that the GI microbiome can synthesize oestrogen from biliary steroids through the enterohepatic circulation. It is reported that Bacillus cereus strain, isolated from gingival plaque, metabolizes the hormone progesterone into 5-alphapregnane-3,20-dione, which is higher in breast tumours than in healthy breast tissue.
Thus, it has a novel role in oestrogen driven cellular proliferation in ER+ breast cancers as well as for the incidence in post-menopausal women. ER+ means the cancer cells grow in response to the hormone oestrogen.
Probiotics and superfoods are becoming increasingly popular in the modern world. Consequently, there is a greater need to understand how probiotics can influence treatment and ultimately the outcome (table 1).
Probiotics are defined as live bacteria and yeasts that can exert a beneficial effect on the host’s health. In recent years, they have been identified to have a role as an anti-cancer agent through protecting DNA from damage, immune modulation, and the suppression of carcinogens.
With the availability of internet, cancer patients have the chance to explore their therapeutics and increase their awareness. There is increasing use of probiotics alongside a treatment regimen. Indeed, it may be beneficial to the individual patient’s quality of life and treatment plan (Table 1).
Table 1: A table examining the potential pros and cons of the use of probiotics alongside a standard treatment regimen of surgery, chemotherapy and radiotherapy.
Pros of probiotics in breast cancer therapy
Cons of probiotics in breast cancer therapy
They are potentially able to replace some of the beneficial bacteria, which are killed through chemotherapy. If used alongside chemotherapy, it could aim to reduce gastrointestinal toxicity.
Probiotic use is associated with a decreased incidence in CTC grade diarrhoea.
Side effects such as mild stomach upset, diarrhoea, or flatulence can happen, but these are often mild. If taken with chemotherapy and radiotherapy regimen, probiotics may pose additional problems affecting the quality of life.
They are low cost and easy to take. They are often widely available in the form of drinks, yoghurts and tablets.
Neutropenia-induced chemotherapy reduces the immune system, which may lead to a secondary infection caused by the bacteria in probiotics.
They may be able to stimulate the immune system against the tumour, inducing cytostatic or even cytotoxic effects.
There could be a potential impact on the efficacy of therapeutics by altering the tumour microenvironment. Clinical trials and studies may not consider dysbiosis when looking at potential drugs.
Probiotics could reduce post-operative inflammation, preventing further progression.
There could be undesired adverse events such as sepsis.
Probiotics may be used as a preventative measure rather than a curative measure because the bacteria can enhance the immune surveillance ability, enabling detection of cancer before it occurs. Lactobacillus has been shown to have a protective effect of cancer development in animal models, but this has not been explored in a clinical trial setting.
Microbe-drug interaction could affect the outcome of the therapeutic regimen. The tumour microenvironment is complex, so altering the microbiome may not have the desired effect. This can also alter the gene expression of the microenvironment and the tumour itself.
To evaluate the safety and efficacy of probiotic use alongside conventional therapy, a meta-analysis was performed on randomised control trials across several countries and cancer types.
Of these 43 trials, no adverse events associated with the consumption of probiotics is identified. Nonetheless, one patient had a potentially related mild hypersensitivity reaction.
This can be attributed to the fact that cancer patients are immunocompromised; thus, probiotic associated infections may be more common.
Furthermore, neutropenia (low neutrophil count) can arise following chemotherapy. Current diet recommendation for neutropenic patients is to avoid products containing probiotics, which is based on bacteraemia case reports and manufacturers' recommendations, rather than robust scientific evidence.
A meta-analysis was carried out to investigate this further. Researchers found that, out of 1530 people within the studies, 105 experienced a wide range of adverse events, including: raised intra-cranial blood pressure, septicaemia and dysphagia.
However, in patients with pelvic malignancies, consumption of probiotics containing Lactobacillus species may help prevent diarrhoea secondary to chemotherapy or radiotherapy. Therefore, specific effects in particular tissues should be taken into consideration.
There is still a lack of sufficient evidence to claim that probiotics have a beneficial effect on cancer patients. Furthermore, their safety should be diligently questioned. Whilst patients may see fit to consume probiotics during treatment, the clinicians should be informed.
The research in this area is still in its infancy, and we will need a greater understanding of the intricacies of the microbiome within normal and malignant tissue.
When achieved, the restoration of healthy microbiome-host relationship may be the goal of therapy and a part of clinical practice.
- Hieken TJ, Chen J, Hoskin TL, Walther-Antonio M, Johnson S, Ramaker S, et al. The Microbiome of Aseptically Collected Human Breast Tissue in Benign and Malignant Disease. Sci Rep [Internet]. 2016 Aug 3;6:30751. Available from: http://dx.doi.org/10.1038/srep30751
- Carding S, Verbeke K, Vipond DT, Corfe BM, Owen LJ. Dysbiosis of the gut microbiota in disease. Microb Ecol Health Dis [Internet]. 2015 Feb 2;26:10.3402/mehd.v26.26191. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4315779/
- Guinane CM, Cotter PD. Role of the gut microbiota in health and chronic gastrointestinal disease: understanding a hidden metabolic organ. Therapy Adv Gastroenterol [Internet]. 2013 Jul;6(4):295–308. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667473/
- Castellarin M, Warren RL, Freeman JD, Dreolini L, Krzywinski M, Strauss J, et al. Fusobacterium nucleatum infection is prevalent in human colorectal carcinoma. Genome Res [Internet]. 2012 Feb 20;22(2):299–306. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3266037/
- Thomas RM, Jobin C. The Microbiome and Cancer: Is the “Oncobiome” Mirage Real? Trends in Cancer [Internet]. 2015;1(1):24–35. Available from: http://www.sciencedirect.com/science/article/pii/S2405803315000060
- Singh B, Berry JA, Shoher A, Ramakrishnan V, Lucci A. COX-2 overexpression increases motility and invasion of breast cancer cells. Int J Oncol. 2005 May;26(5):1393–9.
- Zhao X, Xu Z, Li H. NSAIDs Use and Reduced Metastasis in Cancer Patients: Results from a meta-analysis. Sci Rep [Internet]. 2017;7(1):1875. Available from: https://doi.org/10.1038/s41598-017-01644-0
- Salinas CA, Kwon EM, FitzGerald LM, Feng Z, Nelson PS, Ostrander EA, et al. Use of aspirin and other nonsteroidal antiinflammatory medications in relation to prostate cancer risk. Am J Epidemiol. 2010 Sep;172(5):578–90.
- Lakritz JR, Poutahidis T, Mirabal S, Varian BJ, Levkovich T, Ibrahim YM, et al. Gut bacteria require neutrophils to promote mammary tumorigenesis. Oncotarget [Internet]. 2015;6(11):9387–96. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4496224&tool=pmcentrez&rendertype=abstract
- Uribe-Querol E, Rosales C. Neutrophils in Cancer: Two Sides of the Same Coin. J Immunol Res [Internet]. 2015 Dec 24;2015:983698. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4706937/
- Kwa M, Plottel CS, Blaser MJ, Adams S. The Intestinal Microbiome and Estrogen Receptor-Positive Female Breast Cancer. JNCI J Natl Cancer Inst [Internet]. 2016 Aug 22;108(8):djw029. Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5017946/
- Urbaniak C, Gloor GB, Brackstone M, Scott L, Tangney M, Reid G. The Microbiota of Breast Tissue and Its Association with Breast Cancer. 2016;82(16):5039–48.
- Redman MG, Ward EJ, Phillips RS. The efficacy and safety of probiotics in people with cancer: A systematic review. Ann Oncol. 2014;25(10):1919–29.
- Maroof H, Hassan ZM, Mobarez AM, Mohamadabadi MA. Lactobacillus acidophilus could modulate the immune response against breast cancer in murine model. J Clin Immunol. 2012;32(6):1353–9.