To our best knowledge, this is the first study to assess the relationship between neighborhood disadvantage and markers of biological aging among breast cancer patients. In the study, we reported that breast cancer patients who lived in the area with high ADI had higher median allostatic load levels and lower median global DNA methylation levels. In addition, global DNA methylation was found to mediate 6.52 and 7.98% of the association between ADI with stage III and poorly differentiated tumor grade (P = 0.037 and 0.023). The results from this study shed light on the importance of biological aging in linking neighborhood disadvantage with aggressive breast tumor characteristics and other adverse clinical outcomes.
During the aging process, epigenetic changes, including global DNA hypomethylation and hypermethylation at regions of CpG island, are commonly observed (27). Such changes in the epigenetic landscape may contribute to aging by adversely affecting genomic stability and gene regulation. In this study, we found s statistically significant association between high ADI and decreased levels of global DNA methylation. The possible pathways underlying the is likely to be multifactorial. For example, living in a disadvantaged neighborhood is known to have lower levels of physical activity and a higher likelihood of being overweight or obese. In a meta-analysis of 24 studies, a trend between higher levels of physical activity and higher levels of global DNA methylation was observed (22) and subsequently led to a suggestive association with a reduced breast cancer risk. Furthermore, living in a disadvantaged neighborhood may have increased exposure to certain endocrine disruptors (e.g., BPA and dioxins) (19). It has been known that exposure to endocrine disruptors influences DNA methylation globally and CpG site specifically (28). Interestingly, breast tissue is particularly susceptible to the effects of endocrine disruptors during the development period as well as adulthood (29). In addition, chronic stress is known to induce persistent changes in global DNA methylation and gene expression (30).
The relationship between neighborhood disadvantage and global DNA methylation has rarely been studied. Only one study has been found in the literature. Coker et al. found that pregnant women living in neighborhoods with the highest poverty levels gave birth to infants with higher cord blood LINE-1 methylation compared with pregnant women living in the lowest level of poverty (31). On the contrary, several studies have investigated the gene or CpG site-specific methylation and its relationship with neighborhood disadvantage. For example, in the Multi-Ethnic Study of Atherosclerosis (MESA) study, neighborhood characteristics have been found to influence DNA methylation of genes involved in stress response and inflammation (32). More interestingly, using newly developed epigenetic clocks based on DNA methylation, Lawrence et al. recently reported that residing in a neighborhood with a higher deprivation index had higher epigenetic age acceleration estimated by Hannum, PhenoAge, and GrimAge clocks (33).
The positive association between high ADI and increased allostatic load is consistent with previous reports (34). In a scoping review of 14 studies, most studies (n = 12) reported a significant association between neighborhood deprivation and allostatic load, even after adjustment for confounding variables such as individual socioeconomic status, gender, and age (34). In another study using data from three cohort studies in European countries, a statically significant trend of increasing allostatic load with the increase of area deprivation (P < 0.001) was reported (35). Previous studies also reported that the associations are more pronounced among Blacks, men, and individuals with poor social support. A similar difference by race was observed in our study. We found that the association was stronger among non-Hispanic Black than non-Hispanic White and Mexican American breast cancer patients. To dissect the potential pathways that might help explain the relationships between ADI with global DNA methylation and allostatic load, we also assessed adjustment for healthy behaviors (e.g., tobacco use, alcohol drinking, obesity, and physical inactivity) influenced the association. Though the adjusted associations attenuated slightly, the significant association has remained. Clearly, those healthy behaviors didn’t fully account for the significant association. It is very likely that other pathways in addition to health-related behaviors contribute to the observed associations.
Unlike previous studies, we didn’t observe the significant association between telomere length with neighborhood disadvantage (36) and several neighborhood characteristics measured subjectively and objectively (37–40). In a previous study using the data from the 1999–2002 National Health and Nutrition Examination Survey, neighborhood deprivation was inversely associated with telomere length among individuals living in neighborhoods with medium neighborhood deprivation index (NDI) (P = 0.0005) and high NDI (P = 0.003) (36). However, only medium NDI (P = 0.009) was associated with shorter telomere length among women. One significant discrepancy between our study and those studies is the study population. Unlike those studies, our study population is consistent with women diagnosed with breast cancer. Telomere length has dual role in cancer development. Though critically short telomeres may lead to chromosomal degradation, end-to-end fusion, and abnormal recombination, processes involved in cancer development, cells with longer telomeres may favor delayed cell senescence, thus increasing the chance of developing chromosomal instability and genetic aberrations, eventually leading to carcinogenic transformation (41). In cancer epidemiological studies, both longer or shorter telomere length has been associated with an increased risk of breast cancer (42).
A few studies have examined the relationship between neighborhood disadvantage and breast tumor characteristics. In three Appalachian states, area deprivation is strongly associated with the disparity in the later stage of breast cancer. The most deprived counties had a 3.31 times greater rate of LSBC compared to the least deprived (43). In a recent publication by Babatunde et al., a higher social deprivation index was associated with a distant stage at diagnosis (OR = 1.06, 95% CI: 1.02–1.10) among breast cancer patients (44). We have similar findings in our study. Among breast cancer patients, those from the high ADI group were more likely to develop stage III (P = 0.029) and poorly differentiated breast tumors (P = 0.019). Furthermore, we found that increased global DNA methylation was found to mediate 6.52 and 7.98% of the association between higher ADI group with grade III and poorly differentiated tumor grade (P = 0.037 and 0.023). Our results highlight the role of global DNA methylation in linking neighborhood disadvantage and adverse tumor characteristics among breast cancer patients.
There are several limitations to this study. The study design is cross-sectional, and none of the breast cancer patients included in this study live in the area with an ADI of over 80%. This may limit our statistical power to detect the significant association. It may also reduce our ability to interpret and generalize the findings. Though the study has included non-Hispanic Black and Mexican American breast cancer patients, the number is modest. Thus, we may not have adequate power to assess whether the association differs by race. Additionally, markers of biological aging were measured only once. A single measurement may not reflect the dynamic nature of the relationship between neighborhood disadvantage and biological aging. Nevertheless, the considerable strengths of our study outweigh the limitations. Findings from this study contribute important knowledge on how neighborhood disadvantage may affect breast cancer outcomes through accelerated biological aging. Additional research, particularly addressing the limitations mentioned above, is needed to validate our findings, and further clarify the association.