Hannah Pearson

 Background: One in eight women worldwide will be diagnosed with breast cancer within their lifetime.¹ Upon diagnosis, breast cancer is subdivided into one of four subtypes based on a variety of characteristics – luminal A, luminal B, HER2+, and triple negative. Current treatment includes surgery and radiation, along with more targeted receptor-based therapies.² Several known environmental risk factors for breast cancer including diet, obesity, alcohol consumption and antibiotic exposure also have significant impacts on the gut microbiota profile. As a result, the relationship between the gut microbiome and breast cancer has emerged as an area of new research.³

Objective: In this narrative review, we explored CCL2-driven mast cell accumulation and subsequent fibroblast activation as a potential link between antibiotic-induced gut dysbiosis and tumor progression in breast cancer.

Search Methods: An online search in the PubMed database was conducted from 2018 to 2024 using the keywords: “breast cancer,” “microbiome,” “antibiotics,” “breast cancer metastasis,” “mast cells,” and “fibroblast.”

Results: Multiple studies utilizing antibiotic-induced dysbiotic mice observed increases in mammary tumor dissemination and growth.^4,5,6 Analysis of the mammary glands of dysbiotic mice revealed a significantly elevated mast cell density.^5,6 These mice also had significantly elevated levels of the chemokine CCL2 in their mammary tissue, and the percentage of mast cells expressing the associated receptor, CCR2, was also significantly higher.⁵ When CCL2 was neutralized via a blocking antibody, mast cell density did not differ significantly between the dysbiotic and non-dysbiotic mice, suggesting that CCL2 is an essential link between dysbiosis and mast cell accumulation.⁵ When mast cells were inhibited in dysbiotic mice, mammary tumor volume was significantly lower, indicating that mast cells are a link between the gut and mammary tumor development. Conversely, when cromolyn, a mast cell stabilizer, was used to inhibit mast cells in the control mice, there was no significant difference in tumor volume.⁶

In humans, increased mast cell density has been associated with worsened response to neo-adjuvant chemotherapy, as determined by analysis of breast biopsy samples.⁷ Activated fibroblasts have previously been shown to increase cancer cell invasion of adjacent tissues.⁸ In mouse studies, fibroblast density and activity were found to be significantly elevated in dysbiotic mice.⁵ Mast cell inhibition reduced the fibroblast activity back to control levels in dysbiotic mice, indicating that mast cells in dysbiotic mice drive tumor progression through fibroblast activation.⁵ While specific bacterial species are still being identified, studies currently indicate that antibiotic-induced gut dysbiosis is likely influencing mammary tumor growth via the loss of a protective species, rather than the overgrowth of a harmful microbiota member.⁶

Conclusion: Studies indicate that antibiotic-induced gut dysbiosis increases mammary tumor dissemination and growth in mice.^4,5,6 Gut dysbiosis has been shown to enhance mammary tumor progression in mice, potentially through CCL2.⁵ Consideration of bacterial replacement following antibiotic treatment and the impact of mast cells and/or fibroblast regulation in breast tumorigenesis could yield new treatments, protective approaches, and guidelines for breast cancer.

Works Cited:

1. Michaels E, Worthington RO, Rusiecki J. Breast Cancer: Risk Assessment, Screening, and Primary Prevention. Med Clin North Am. 2023;107(2):271-284. doi:10.1016/j.mcna.2022.10.007
2. Orrantia-Borunda E, Anchondo-Nuñez P, Acuña-Aguilar LE, Gómez-Valles FO, Ramírez-Valdespino CA. Subtypes of Breast Cancer. PubMed. Published 2022. https://www.ncbi.nlm.nih.gov/books/NBK583808/
3. Teng NMY, Price CA, McKee AM, Hall LJ, Robinson SD. Exploring the impact of gut microbiota and diet on breast cancer risk and progression. Int J Cancer. 2021;149(3):494-504. doi:10.1002/ijc.33496
4. Buchta Rosean C, Bostic RR, Ferey JCM, et al. Preexisting Commensal Dysbiosis Is a Host-Intrinsic Regulator of Tissue Inflammation and Tumor Cell Dissemination in Hormone Receptor-Positive Breast Cancer. Cancer Res. 2019;79(14):3662-3675. doi:10.1158/0008-5472.CAN-18-3464
5. Feng TY, Azar FN, Dreger SA, et al. Reciprocal Interactions Between the Gut Microbiome and Mammary Tissue Mast Cells Promote Metastatic Dissemination of HR+ Breast Tumors. Cancer Immunol Res. 2022;10(11):1309-1325. doi:10.1158/2326-6066.CIR-21-1120
6. McKee AM, Kirkup BM, Madgwick M, et al. Antibiotic-induced disturbances of the gut microbiota result in accelerated breast tumor growth. iScience. 2021;24(9):103012. Published 2021 Aug 20. doi:10.1016/j.isci.2021.103012
7. Reddy SM, Reuben A, Barua S, et al. Poor Response to Neoadjuvant Chemotherapy Correlates with Mast Cell Infiltration in Inflammatory Breast Cancer. Cancer Immunol Res. 2019;7(6):1025-1035. doi:10.1158/2326-6066.CIR-18-0619