Breast cancer is a major health challenge for women worldwide, and its etiology is complex and diverse [2]. Currently, clinical therapeutic strategies are mainly based on the classification of estrogen receptor (ER) and human epidermal growth factor receptor 2 (HER2) status [6]. The classification of breast cancer subtypes is closely related to the expression of ER and HER2 receptors, and it is important to explore the pathogenic factors of breast cancer subtypes for clinical prevention and treatment. Autoimmune diseases such as dry syndrome, rheumatoid arthritis and systemic lupus erythematosus have a high prevalence in women, while breast cancer is the most common malignant tumor in women [30, 31]. To investigate whether there is a correlation between the two, we conducted the present study.

The findings indicate a reduced risk of breast cancer in patients with Sjögren’s syndrome, idiopathic inflammatory myopathy, and rheumatoid arthritis, showing odds ratios(OR) of 0.96 (95% CI [0.93–0.99], p = 0.011), 0.98 (95% CI [0.97–0.99], p = 0.035), and 0.98 (95% CI [0.96–1.00], p = 0.050), respectively. The observed protective effect of Sjögren's syndrome on breast cancer risk corroborates Jian Deng's research findings [32].

Moreover, the study delved into the association between autoimmune diseases and breast cancer across different HER and ER expression states. It revealed that systemic lupus erythematosus significantly reduces the risk of HER- breast cancer (OR = 0.95, 95% CI [0.91–0.99], p = 0.046). Idiopathic inflammatory myopathy significantly lowered the risk of HER + breast cancer (OR = 0.96, 95% CI [0.93–0.99], p = 0.036). Sjögren's syndrome and rheumatoid arthritis also appeared to act as protective factors against HER + breast cancer, with statistically significant differences observed (Sjögren's syndrome, OR = 0.90, 95% CI [0.83–0.98], p = 0.02; Rheumatoid arthritis, OR = 0.94, 95% CI [0.91–0.98], p = 0.006).

Notably, the analysis on the correlation between systemic sclerosis and HER- breast cancer yielded a p-value close to 0.05 (p = 0.06), suggesting a non-significant statistical difference. However, this trend might still indicate a protective effect in patients with HER- breast cancer. The relationship between systemic sclerosis and breast cancer warrants further exploration in future studies as the database expands and more data become available.

According to the results of this study, autoimmune diseases may reduce the risk of developing breast cancer. We believe that the specific mechanisms are as follows. Firstly, the “immunosurveillance” hypothesis proposes that autoimmune diseases are due to an increase in immune tone, which improves immunosurveillance [33].

Immune surveillance refers to the immune system's process of recognizing and eliminating abnormal cells, such as cancer cells, which includes the phases of elimination, equilibrium, and escape [34]. Research indicates that tumors can be recognized by the immune system and controlled or prevented through immune surveillance processes [35]. The specificity of tumor immune responses lies in the recognition of tumor antigens. The immune system identifies and clears nascent tumors by recognizing tumor-specific neoantigens expressed on tumor cells, similar to allograft rejection, thus maintaining tissue homeostasis in complex multicellular organisms [34, 36]. In clinical settings, the restoration of immune surveillance is considered a measure of the effectiveness of chemotherapy, targeted therapy, and radiotherapy in breast cancer patients [37].

Supporting this, studies have shown that individuals with broad autoantibody specificity can decrease their risk of breast cancer by 60% [38]. Additionally, research has reported a decreased risk of breast cancer in patients with systemic lupus erythematosus (SLE), which may be associated with anti-DNA antibodies. These antibodies exert direct anti-cancer effects on cells with DNA repair deficiencies [38]. This aligns with findings that systemic lupus erythematosus significantly lowers breast cancer risk, which is consistent with the results of this study [39]. Further mechanistic studies have revealed that a cell-penetrating lupus autoantibody (3E10) is synthetically lethal to BRCA2-deficient human cancer cells and can enhance the effectiveness of low doses of doxorubicin, thereby improving chemotherapy outcomes [40]. Additionally, James Gardner Thorpe's study reported that lupus-associated anti-ribosome P autoantibodies could directly induce apoptosis in cancer cells [41]. From the treatment perspective of autoimmune diseases, certain studies have noted that using non-steroidal anti-inflammatory drugs or aspirin can boost tumor immune surveillance and lower cancer risk [42, 43]. On the contrary, glucocorticoid use may disrupt immune surveillance and elevate cancer risk [44].

Previous studies on Sjögren’s syndrome (SS) have consistently reported a decreased incidence of breast cancer, which aligns with our findings. Hemminki et al. compared 1516 Swedish SS patients with the general population, noting a standardized incidence ratio (SIR) for breast cancer of 0.46 (95% confidence interval: 0.26–0.75) [45]. Several factors may explain the lower risk of breast cancer in SS patients. SS primarily affects exocrine glands, especially the lacrimal and salivary glands, which share anatomical, histological, and immunological similarities with the breast. SS patients display different immune patterns in breast-associated mucosal tissues, with higher proportions of CD4 + T cells. This suggests a distinct immune response to local antigens, such as tumor cells, potentially establishing a more robust mucosal immune system dynamic that may reduce breast cancer incidence [45, 46]. Additionally, studies have identified lower estrogen levels in SS patients, which significantly contribute to reducing breast cancer incidence [47]. Estrogen is a known risk factor for breast cancer development, so lower estrogen levels may provide protective effects against the disease.

Our findings suggest that rheumatoid arthritis may reduce the risk of developing HER + breast cancer. It has been shown that rheumatoid arthritis (RA) may reduce breast cancer risk, which is consistent with our findings [48]. The mechanisms may include the following: Firstly, the peak incidence of female RA often occurs during menopause, characterized by decreased hormone secretion, including estrogen. Lower estrogen levels are known to reduce breast cancer risk. Furthermore, studies have demonstrated significant differences in luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels between RA patients and healthy individuals. These hormones are crucial in regulating reproductive function and sex hormone levels, and their fluctuations may further influence breast cancer risk [49]. In cohorts of patients with idiopathic inflammatory myopathies, reports indicate that individuals with breast and ovarian cancers often carry anti-synthetase antibodies, which possess anticancer properties [50, 51]. These observations suggest a complex interplay between autoimmunity and cancer incidence, necessitating further exploration through in vivo and in vitro studies. Overall, these findings highlight the significant role of the immune system and autoimmune diseases in regulating breast cancer risk.

However, to date, no significant link between ER + and ER- breast cancer and autoimmune diseases has been established in genome-wide association studies (GWAS) using European population samples. Future updates to these databases may provide opportunities for more in-depth exploration of this relationship. This study has several strengths: Primarily, it is the first to utilize Mendelian Randomization (MR) to investigate potential causality between autoimmune diseases and breast cancers with varying HER and ER states. MR methodology significantly minimizes the effects of confounding factors and reverse causation. Compared to traditional observational studies, the analysis of single nucleotide polymorphisms (SNPs) reduces the impact of multiple potential confounders, offering more robust research evidence.

Nonetheless, there are limitations to this study. First, the sample predominantly consisted of the European population. Whether these findings are applicable to other regions and populations remains uncertain, necessitating further validation in diverse populations and regions. Secondly, the potential for pleiotropy is an issue that cannot be entirely ruled out in MR studies and requires additional investigation and discussion. Furthermore, due to variations in data collection times, disease progression stages, and treatment phases in GWAS data, our study has some limitations. These factors may affect the research outcomes to a certain extent, but we can still derive valuable SNP data analysis results from them. Further, our study is based on genome-wide association study (GWAS) data, revealing potential genetic factors in relation to disease. However, these findings are limited to statistical associations and do not provide direct mechanistic causality. Therefore, our findings need to be validated by in vivo experiments in future studies to further reveal the underlying biological mechanisms.