Systemic and local chronic inflammation and hormone disposition promote a tumor-permissive environment for breast cancer in older women

作者：Neil Carleton, Alexander Chih-Chieh Chang, Sanghoon Lee, Ruxuan Li, Jian Zou, Daniel D. Brown, Jagmohan Hooda, Jian Chen, Rahul Kumar, Linda R. Klei, Lora H. Rigatti, J. Newsome, Dixcy Jaba Sheeba John Mary, Jennifer M. Atkinson, Raymond E. West, Thomas D. Nolin, Patrick J. Oberly, Ziyu Huang, Donald Poirier, Emilia J Diego, Peter C. Lucas, George C. Tseng, Michael T. Lotze, Priscilla F. McAuliffe, Ioannis K. Zervantonakis, Steffi Oesterreich, Adrian V. Lee · 发表于：Nature Aging · 年份：2026 · DOI：10.1038/s43587-026-01173-4 · 被引用次数：2 · 研究领域：Immune cells in cancer、Cancer Immunotherapy and Biomarkers、Chemokine receptors and signaling

Abstract Estrogen receptor positive (ER+) breast cancer is the most common subtype of breast cancer and is an age-related disease. The peak incidence of diagnosis occurs around age 70, even though these post-menopausal patients have low circulating levels of estradiol (E2). Despite the hormone sensitivity of age-related tumors, we have a limited understanding of the interplay between systemic and local hormones, chronic inflammation, and immune changes that contribute to the growth and development of these tumors. Here, we show that aged F344 rats treated with the dimethylbenz(a)anthracene / medroxyprogestrone acetate (DMBA/MPA) carcinogen develop more tumors at faster rates than their younger counterparts, suggesting that the aged environment promotes tumor initiation and impacts growth. Single-nuclei RNA-seq (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 an estrone (E1)-predominant estrogen disposition in the systemic circulation, tumors in older patients increase HSD17B7 expression to convert E1 to E2 in the tumor microenvironment (TME) and have local E2 levels similar to pre-menopausal patients. Concurrently, trackable increases in several chemokines, defined most notably by CCL2, promote a chronically inflamed but immune dysfunctional TME. This unique m...