Exploring the Impact of Endocrine-Targeting Therapies on Breast Microbiota and Their Potential in Breast Cancer Prevention and Treatment

Breast cancer is one of the most commonly diagnosed types of cancer in women. Despite significant advancements in diagnosis and treatment, the mortality rate remains high, with over 40,000 deaths annually in the United States alone. Hormone receptor-positive breast cancer, which expresses estrogen receptor (ER) and/or progesterone receptor, accounts for 60%-70% of all breast cancer cases and has become a key focus of research. Recent studies have suggested that breast tissue contains a unique and modifiable microbiota, which may regulate tumorigenesis and therapeutic sensitivity, opening a new direction for research.

This study builds on this background, aiming to investigate the diversity of breast tissue microbiota, changes in its metabolic functions, and its relationship with breast cancer risk and endocrine therapy responses. Conducted by Katherine L. Cook and her colleagues at Wake Forest University, the research findings were published on January 21, 2025, in Cell Reports Medicine under the title “Endocrine-targeting therapies shift the breast microbiome to reduce estrogen receptor-a breast cancer risk.”

Study Background and Objectives

Recent evidence indicates that breast tissue is not sterile but hosts a rich microbiota, whose composition may play a significant role in breast cancer development and treatment. For instance, dysbiosis of the breast microbiome is associated with carcinogenic factors such as inflammation, immune evasion, and genetic instability. However, it remains unclear how endocrine-regulating therapies, such as Tamoxifen, influence the breast microbiome to affect tumorigenesis and treatment outcomes. Through multi-model research, this study explores microbiota composition, metabolic mechanisms, and their potential impact on breast cancer development.

Detailed Research Design

Subjects and Experimental Design

This study involves multiple layers of experiments, including animal models (mice and ovariectomized non-human primates), histological analysis, microbiome genomic profiling, metabolomics studies, and cellular experiments.

1. Effect of Tamoxifen on Breast Microbiota Composition

The study first examined whether Tamoxifen alters breast microbiota in an ovariectomized non-human primate model. Using DNA sequencing technology (16S rRNA sequencing), the team analyzed microbiota composition in breast tissue. The experiments showed that Tamoxifen significantly changed the β-diversity of the microbiota, with significant increases in beneficial bacteria such as Lactobacillus spp. Meanwhile, changes in the abundance of the phylum Proteobacteria were not significant. Immunohistochemical analysis revealed a marked increase in lipoteichoic acid-positive (LTA-positive, Gram-positive bacteria marker) bacteria following Tamoxifen treatment, whereas lipopolysaccharide-positive (LPS-positive, Gram-negative bacteria marker) bacteria showed no significant changes.

2. Interactions Between Diet, Microbiota, and Drug Treatments

To further investigate the interactions between diet and drug treatments on the breast microbiome, the researchers used a mouse model and designed experiments with different dietary backgrounds (healthy diet and Western diet). Tamoxifen enhanced the proportion of Lactobacillus spp. in breast tissue under a healthy diet, but increased Proteobacteria under a Western diet. These findings suggest that drug effects interact with dietary backgrounds to produce different impacts on microbiota diversity.

3. Localized Probiotic Injections and Breast Cancer Risk

The research also examined whether localized probiotic injections in the breast could reduce breast cancer risk. In the B6.MMVT-PyMT mouse model, localized injections of Lactobacillus and other probiotics significantly reduced tumor multiplicity and extended survival times. These changes in local microbiota were accompanied by altered expression of metabolic genes in the breast, especially those associated with glucose metabolism. Furthermore, analysis of tumor samples from breast cancer patients revealed that LTA-positive bacteria inversely correlated with tumor proliferation during endocrine therapy.

4. Cell Experiments and Metabolomics Analysis

To understand the impact of probiotic metabolites on cellular metabolism, the researchers conducted experiments using non-cancerous mammary epithelial cell lines (S1 cells) and ER+ breast cancer cell lines (MCF-7 and ZR-75-1). Probiotic-secreted metabolites significantly enhanced oxygen consumption rates and glycolysis activity in non-cancerous cells, while suppressing oxygen consumption in cancer cells. Further validation showed that probiotic-derived metabolites, such as trehalose, inhibited tumor growth both in vitro and in vivo.

Major Findings of the Study

The study yielded several innovative conclusions:
1. Endocrine-targeting therapies like Tamoxifen reduce breast cancer risk by modulating the breast microbiome, particularly by increasing Lactobacillus and Streptococcus populations.
2. Localized probiotic administration in the breast showed significant potential for reducing tumor risk.
3. Probiotic-secreted metabolites can regulate metabolism in normal breast cells while suppressing cancer cell metabolism.
4. Combining Tamoxifen with probiotics demonstrated synergistic therapeutic potential.

Significance and Research Implications

This study highlights the importance of the breast microbiome as a potential therapeutic target and reveals the complex interactions between treatments and microbiota. It provides scientific evidence for enhancing therapy by modulating the microbiota. Notably, the novel application of localized probiotics opens new avenues for personalized medicine and preventive strategies in breast health.

The study also identifies several directions for future clinical research, such as evaluating the colonization effects of probiotics in breast tissue via non-invasive methods and elucidating the mechanisms by which probiotic-secreted metabolites act. These further investigations could pave the way for groundbreaking advancements in cancer prevention and treatment.