Gut Microbiota and Immune Response in Breast Cancer Progression

Exploring the Gut-Immune-Cancer Axis in Breast Cancer Risk

Breast cancer is one of the most common malignancies affecting women worldwide and remains a leading cause of cancer-related deaths. According to the article published in Biomolecules and Biomedicine by Zhang et al., the disease affects approximately one in eight women in the United States during their lifetime. The risk of breast cancer increases with age—about 0.5% per year—and has been linked to both genetic mutations (such as BRCA1 and BRCA2) and lifestyle factors like diet and obesity.

Despite improvements in early detection and advances in treatments—ranging from surgery to targeted and endocrine therapies—advanced breast cancer remains difficult to treat and is often associated with significant side effects. The biological mechanisms driving breast cancer are still not fully understood, which makes prevention and effective interventions challenging.

In recent years, the gut microbiota—the community of microorganisms living in our intestines—has gained attention for its potential role in various diseases, including cancer. This microbiome co-evolves with the human body, helping regulate metabolic and immune functions. Disruption of this balance, known as dysbiosis, has been linked to immune-related diseases and potentially to cancer development. However, the causal role of specific microbes in breast cancer has remained uncertain.

New Study Uses Genetic Data to Explore Microbial Influence

To better understand this connection, Zhang et al. conducted a large-scale Mendelian Randomization (MR) study that investigated whether certain gut microbiota directly affect the risk of developing breast cancer and whether immune cells mediate this effect. The study involved genome-wide association data for:

• 412 gut microbiota taxa and pathways

• 731 immune cell traits

• Three breast cancer groups: overall, HER2-positive, and HER2-negative subtypes

The authors employed two-sample MR, which uses genetic variants as natural experiments to infer causality between exposures (e.g., microbial pathways) and outcomes (e.g., cancer). This approach reduces the influence of confounding factors that often affect observational studies. They also used Bayesian Weighted Mendelian Randomization (BWMR) to confirm the robustness of their findings.

Microbial Pathways Linked to Breast Cancer Risk

The results showed 15 microbial traits—including both bacterial taxa and metabolic pathways—were significantly associated with overall breast cancer risk:

• 9 had positive associations (i.e., increased risk)

• 6 had negative associations (i.e., reduced risk)

Some of the microbial pathways that increased risk included:

• PWY-6263: superpathway of menaquinol-8 biosynthesis II

• PRPP-PWY: histidine, purine, and pyrimidine biosynthesis

• DAPLYSINESYN-PWY: L-lysine biosynthesis I

In contrast, protective pathways included:

• FAO-PWY: fatty acid beta-oxidation

• PWY-4984: urea cycle

• PWY-5005: biotin biosynthesis II

Among microbial taxa, Pseudoflavonifractor and Parabacteroides merdae were positively associated with cancer risk, while Roseburia and Bacteroides intestinalis showed protective effects.

Breast Cancer Subtypes Reveal Microbial Specificity

Because breast cancer is a heterogeneous disease, the study also analyzed data separately for HER2-positive and HER2-negative subtypes. The associations varied:

• For HER2-positive breast cancer, 8 microbial pathways and 11 taxa showed significant associations.

• For HER2-negative breast cancer, 10 pathways and 6 taxa were implicated.

Interestingly, the biotin biosynthesis II pathway was negatively associated (i.e., protective) in both total breast cancer and the HER2− subtype, suggesting a potentially broad role in breast cancer prevention.

Immune Cells May Mediate Microbial Effects

A key innovation in the study was examining whether immune cells act as mediators in the microbiota–breast cancer relationship. Using mediation analysis, the authors identified several immune cell types that may explain part of the observed microbial effects.

For example, the pathway menaquinol-8 biosynthesis II (PWY-6263) increased breast cancer risk, but part of this effect was mediated through a type of immune cell called CD4+CD8+ double-positive (DP) T cells. These are a unique subset of T cells involved in immune regulation and have previously been found in patients with metastatic breast cancer in the pleural cavity.

In total:

• DP T cells mediated effects for both total breast cancer and HER2+ subtype

• IgD−CD27− B cells and BAFF-R on CD20− cells acted as negative mediators, suggesting a protective immune function

Although the mediation effects were modest (e.g., 12.6% of the PWY-6263 effect mediated by DP T cells), the findings support the concept that gut microbes may influence cancer risk through immune pathways.

Supporting Evidence from Bayesian Analysis

To confirm these associations, the researchers performed BWMR, which validated that the microbial features identified by two-sample MR were still significant after adjusting for potential confounding. Notably, the biotin biosynthesis II pathway remained significantly associated with all cancer types examined, reinforcing its potential as a protective factor.

Additionally, the authors explored genes linked to the biotin pathway. Several genes—such as RPA2, ATG13, and SCAMP5—were found to be positively associated with breast cancer risk, while others like MSH2 and C1QTNF9 were negatively associated. These gene-level insights suggest potential molecular targets for future investigation.

Practical Implications and Next Steps

The findings open several potential research and clinical avenues:

• Preventive strategies: Modifying the gut microbiota through diet, probiotics, or other interventions may reduce breast cancer risk.

• Therapeutic targeting: Immune pathways affected by specific microbes could be considered in developing treatments, especially for HER2 subtypes.

• Biomarker development: Microbial and immune signatures may help identify individuals at higher risk or guide personalized interventions.

The authors caution that the findings are specific to individuals of European ancestry, as all GWAS datasets used in the study were from European populations. They also noted that the breast cancer subtypes were limited to HER2-positive and HER2-negative, excluding others like triple-negative or Luminal A/B. Future research should explore these additional subtypes and include more diverse populations.

Conclusion

This study presents compelling genetic evidence for a causal link between gut microbiota and breast cancer, partly mediated by immune cell populations. By identifying specific microbial pathways and immune cells involved in the disease process, the research highlights new directions for understanding breast cancer risk and developing targeted interventions.

Although more experimental work is needed to confirm these findings, the research underscores the complexity of the gut–immune–cancer relationship and lays important groundwork for microbiome-informed strategies in breast cancer prevention and treatment.

 

The translation of the preceding English text in Chinese:

 

探索肠道-免疫-癌症轴与乳腺癌风险之间的关系

乳腺癌是全球女性中最常见的恶性肿瘤之一，仍然是导致癌症相关死亡的主要原因之一。根据Zhang等人发表在《Biomolecules and Biomedicine》上的文章，这种疾病在美国女性中一生中大约有八分之一的患病几率。乳腺癌的风险随着年龄增长而增加——大约每年增加0.5%——同时也与遗传突变（如BRCA1和BRCA2）以及饮食、肥胖等生活方式因素有关。

尽管早期筛查和从手术到靶向和内分泌治疗等多种治疗手段取得了进展，但晚期乳腺癌仍然难以治愈，常伴有显著的副作用。乳腺癌的生物学机制尚未被完全理解，这为预防和有效干预带来了挑战。

近年来，肠道菌群——即寄居于人类肠道中的微生物群体——因其在多种疾病（包括癌症）中的潜在作用而受到关注。肠道菌群与人体共同进化，有助于调节代谢和免疫功能。该平衡一旦被打破（称为菌群失调），可能与免疫相关疾病甚至癌症的发生有关。然而，某些特定微生物在乳腺癌中的因果作用尚不明确。

新研究利用遗传数据探索微生物影响

为了更好地理解这种联系，Zhang等人开展了一项大规模孟德尔随机化（Mendelian Randomization, MR）研究，探讨某些肠道微生物是否直接影响乳腺癌的发生风险，并评估免疫细胞是否在其中起到中介作用。研究所用的全基因组关联分析（GWAS）数据包括：

• 412种肠道微生物分类群和代谢通路

• 731种免疫细胞特征

• 三类乳腺癌人群：总体、HER2阳性和HER2阴性亚型

作者使用了双样本MR方法，该方法利用遗传变异作为自然实验，推断暴露因素（如微生物代谢通路）与结局（如癌症）之间的因果关系，从而减少混杂因素的干扰。他们还应用了贝叶斯加权孟德尔随机化（Bayesian Weighted Mendelian Randomization, BWMR）方法来验证结果的稳健性。

与乳腺癌风险相关的微生物通路

研究发现，有15种微生物特征（包括菌群分类和代谢通路）与乳腺癌总体风险显著相关：

• 其中9种与乳腺癌风险增加有关

• 6种则显示出保护作用（风险降低）

风险增加的微生物代谢通路包括：

• PWY-6263：甲萘醌-8生物合成II超级通路

• PRPP-PWY：组氨酸、嘌呤和嘧啶的生物合成

• DAPLYSINESYN-PWY：L-赖氨酸生物合成I

具有保护作用的通路包括：

• FAO-PWY：脂肪酸β-氧化通路

• PWY-4984：尿素循环通路

• PWY-5005：生物素生物合成II通路

在微生物分类方面，**假黄双杆菌（Pseudoflavonifractor）和Merdae副拟杆菌（Parabacteroides merdae）与乳腺癌风险升高相关，而玫瑰杆菌（Roseburia）和肠道拟杆菌（Bacteroides intestinalis）**则具有潜在保护作用。

乳腺癌亚型揭示微生物特异性

考虑到乳腺癌是一种异质性疾病，研究还分别分析了HER2阳性和HER2阴性亚型的相关数据，发现两者之间的微生物关联差异显著：

• 对于HER2阳性乳腺癌，有8条微生物通路和11种菌群与其显著相关

• 对于HER2阴性乳腺癌，有10条通路和6种菌群相关

值得注意的是，生物素生物合成II通路在总体乳腺癌和HER2阴性亚型中均显示负相关（具有保护作用），提示该通路可能具有广泛的预防潜力。

免疫细胞可能在微生物影响中起中介作用

本研究的一大创新是评估免疫细胞是否在肠道菌群影响乳腺癌风险中发挥中介作用。通过中介分析，作者发现几种免疫细胞可能解释部分微生物影响：

例如，**甲萘醌-8生物合成II通路（PWY-6263）会增加乳腺癌风险，但这种影响部分是通过一种名为CD4+CD8+双阳性T细胞（DP T cells）**的免疫细胞实现的。这类细胞参与免疫调节，先前曾在乳腺癌胸腔转移患者中发现。

具体而言：

• DP T细胞在总体乳腺癌和HER2阳性亚型中都具有中介作用

• IgD−CD27− B细胞和CD20−细胞上的BAFF-R具有负向中介作用，显示出一定的免疫保护功能

尽管中介效应较小（例如PWY-6263通路中DP T细胞的中介效应为12.6%），但这些发现支持“肠道菌群通过免疫途径影响癌症风险”的理论。

贝叶斯分析提供支持性证据

为验证相关性，研究者使用BWMR方法校正混杂因素后，发现由双样本MR识别出的微生物特征仍然具有显著意义。特别是生物素生物合成II通路在所有乳腺癌类型中仍显著，强化了其作为保护因子的潜力。

此外，作者还探索了与该通路相关的基因。有些基因（如RPA2、ATG13和SCAMP5）与乳腺癌风险正相关，而另一些基因（如MSH2和C1QTNF9）与风险负相关。这些基因层面的发现为未来研究提供了潜在的分子靶点。

实际意义与未来方向

该研究为多个研究和临床方向打开了可能性：

• 预防策略：通过饮食、益生菌等方式调节肠道菌群，可能有助于降低乳腺癌风险

• 治疗靶点：某些微生物影响的免疫通路可能成为HER2相关亚型治疗的新方向

• 生物标志物开发：微生物和免疫特征或可帮助识别高风险人群并引导个体化干预

作者指出，该研究数据主要来自欧洲人群，因此结果的适用性可能受限。研究还仅限于HER2阳性和HER2阴性乳腺癌，未涉及如三阴性或Luminal A/B等亚型，未来应拓展研究范围并涵盖更多族群。

结论

本研究提供了有力的遗传学证据，支持肠道微生物与乳腺癌之间存在因果关系，这种联系部分通过免疫细胞介导。通过识别相关的微生物通路和免疫细胞，该研究为深入理解乳腺癌风险和发展靶向干预提供了新方向。

尽管仍需进一步的实验研究加以验证，这项研究强调了“肠道-免疫-癌症”关系的复杂性，并为未来基于微生物组的乳腺癌预防和治疗策略奠定了重要基础。

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Reference:

Xiaofang Zhang, Na Ma, Conghui Jin, Xiaoli Cao

Role of gut microbiota and immune response in breast cancer progression.

Biomol Biomed [Internet]. 2025 Apr. 14 [cited 2025 Jun. 20];

Available from: https://www.bjbms.org/ojs/index.php/bjbms/article/view/12003

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