This study evaluated the causal relationship between EMS and breast cancer using a Mendelian randomization approach. We found that each SD increase in EMS predicted a 5.0% decrease in breast cancer risk. The inference still held in the subtype analysis; in patients with ER + breast cancer, each SD increase in EMS predicted a decrease in the risk of breast cancer by 8.1%; however, no causal relationship was observed in ER– patients. In addition, to exclude the possibility that this causal inference received confounding factors, potential confounding factors, such as obesity and smoking, were analyzed. Consequently, we considered that confounding factors did not confound the causal inference.
Despite being benign, EMS also has the characteristics of a malignant tumor 13. Many studies have investigated the relationship between EMS and breast cancer; however, no consistent conclusion has been reached. Some studies have confirmed that EMS increases the risk of breast cancer 14 15,16. Few studies considered EMS protective against breast cancer 7,17,18. Other studies have argued that there is no relationship between EMS and breast cancer 19 20. The possible selection and detection biases in these studies could significantly hamper the data assessment. For example, the selection of women undergoing endometrial surgery in some studies has led to potential selection bias. Additionally, the choice to use a discharge diagnosis of EMS contributed to detection bias, as only severe cases were included in the study. Selection and detection bias excluded many patients with cancer from the study, which might have led to an inaccurate assessment of EMS developing into breast cancer. Simultaneously, some studies used a self-reported format (telephone callbacks and questionnaires), which may have led to recall bias.
The fundamental pathological change in EMS is not proliferation of epithelial cells, but an increase in inflammation and cell survival resulting from apoptosis or diminished differentiation 21. Inflammatory responses due to overproduction of reactive oxygen species are also present in breast cancer patients 22. One study reported that women who underwent bilateral oophorectomy with hysterectomy because of EMS experienced a 58% decrease in breast cancer risk. This might be owing to an early interruption of the inflammatory process that could lead to breast cancer risk 23.
The function of estrogen is mediated by two estrogen receptors (ERα and ERβ). Studies on EMS have shown increased levels of ERβ and decreased levels of ERα in endometriotic tissue compared to that in the normal endometrium 24,25. Reduced methylation of CpG islands in the ERβ gene promoter leads to increased expression levels in endometrial stromal cells, whereas hypermethylation silences ERβ expression. ERβ in endometrial stromal cells dominated the ERα promoter and deregulated its activity, which facilitated the suppression of ERα levels, leading to an altered ERβ:ERα ratio in tissues 26. It was shown that in breast cancer, the expression of ERβ was decreased compared to that in normal tissues, suggesting a protective effect of ERβ against ERα-induced overproliferation 27. Women diagnosed with EMS in the postmenopausal period have an increased risk of breast cancer. It is possible that a higher Erβ level in women with EMS leads to a better prognosis. Our study also found a protective effect of EMS against ER + breast cancer but not against ER– breast cancer.
The consensus among clinicians and researchers is that estrogen increases the risk of laparoscopically visible EMS and associated pelvic pain, and that targeting cyclooxygenase-2 in the estrogen biosynthesis pathway and the prostaglandin pathway decreases or eliminates laparoscopically visible EMS and pelvic pain 28,29. Women younger than 40 years of age had a reduced risk of developing breast cancer when diagnosed with EMS compared with women older than 40 years. The reduced risk among younger women may be because of their exposure to anti-estrogenic drugs. The increased risk in menopausal women may be owing to a common risk factor between postmenopausal EMS and breast cancer 15. Thus, the use of anti-estrogen drugs in patients with EMS might reduce the risk of breast cancer.
It has been shown that when comparing DNA repair capacity (DRC) in both EMS and breast cancer, women with EMS were 10% less likely to have low DRC compared to women without EMS, and those diagnosed with EMS at 38 years of age were 40% less likely to have low DRC. A low DRC is an important risk factor for breast cancer, as reported in the literature and in the same group of women. The mechanisms associated with the protection of breast cancer by EMS and the positive association between EMS and DRC remain largely unknown. Some drugs may also alter DRC, indirectly affecting the risk of breast cancer. As more is known about the molecular similarities between EMS and breast cancer, this knowledge should provide more effective strategies to prevent and treat both conditions 17.
The standardized incidence of in situ breast cancer increased in the 40- to 59-year-old age group; however, patients with EMS aged 40 years or older might undergo breast imaging more frequently than the general population, which could potentially increase the detection and prompt treatment of in situ cancer and thus reduce breast cancer risk 30.
This study has several strengths. The MR analysis was used for the first time to evaluate the causal association between EMS and breast cancer. Since genetic mutations are inherited from the parental generation, they do not receive external environmental influences and are therefore not subject to reverse causality, which is often present in observational studies. Additionally, we excluded the influence of potential confounding factors. Moreover, we derived these data from published GWAS data. The GWAS data contained 2,953 cases and 68,969 controls, which is a large sample size that made our study more convincing.
This study also has some limitations. First, our study indicated that EMS reduced the risk of breast cancer and provided more insight into the clinical disease. However, this has limitations in clinical application since one cannot make people with a high risk of breast cancer develop EMS, which would be difficult to achieve and unethical. Second, only a weak protective effect was observed. Third, our study population was limited to European ancestors, and further studies are needed to determine whether this is feasible in other populations.
In conclusion, these findings provide evidence of an association between EMS and reduced breast cancer risk, with the strongest correlation observed in ER + breast cancer. These results are in agreement with those of our previous analysis of a large pooled epidemiological study. Further studies are needed to understand the mechanisms underlying this association.