Systemic and breast chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women (Human Bulk RNA-Seq)

Estrogen receptor positive (ER+) breast cancer, the most common subtype of breast cancer, is an age-related disease, with the peak incidence of diagnosis occurring around age 70 despite low circulating levels of estradiol. Despite the hormone sensitivity of these age-related tumors, our understanding of the interplay between the systemic and local hormonal disposition and chronic inflammaging is limited. We show that aged F344 rats treated with the DMBA/MPA carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment accelerates tumor growth. snRNA-seq of the tumors showed broad local immune dysfunction that was associated with circulating chronic inflammation. Across a broad cohort of specimens from patients with ER+ breast cancer and age-matched donors of normal breast tissue, we observe that even with E1-predominant estrogen disposition in the systemic circulation, tumors in older patients upregulate HSD17B7 expression to convert E1 to E2 in the TME. Age-related accumulation of tumor-associated macrophages serve as signaling hubs that integrate the E2 and chemokine-driven chronic inflammatory signaling in the TME, which polarize TAMs towards a CD206+/PD-L1+, immunosuppressive phenotype. Overall, these findings suggest that the host’s chronic inflammation and hormonal disposition shape the local tumor microenvironment and are critical contributors to the age-related nature of ER+ breast cancer development and growth.