title	author	format	editor
chronic inflammation and hormone disposition in breast cancer of older women	Neil Carleton	qmd	R

Chronic inflammation and hormone disposition promote a tumor-permissive locale for breast cancer in older women

• Despite the hormone sensitivity of older age-related tumors, our understanding of the interplay between the systemic and local hormonal disposition and chronic inflammation 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 chronic inflammation and hormonal disposition are critical contributors to the age-related nature of ER+ breast cancer development and growth.

Carleton et al. 2024 BioRxiv, [Link here]

Translational Relevance

Paradoxically, ER+ breast cancer is an age-related disease, with the peak incidence occurring around the age of 67-70 years old, despite low circulating levels of estrogens. Here, we show that the unique features of the aged breast TME permit a conducive locale, including high local E2 and an immune dysfunctional environment due to chronic inflammation, for tumor development and growth. Our findings suggest that tumor-associated macrophages integrate the estrogen and chemokine-driven inflammation, polarize toward an immunosuppressive, and drive T cell exclusion. Our results provide evidence to support pharmacologically targeting immune components to re-polarize the aged tumor-immune microenvironment.

Sequencing data analysis

1. Human breast cancer bulk RNA-seq data analysis, GSE276755 https://github.com/leeoesterreich/BRCA_OlderWomen_BulkRNAseq
2. Rat bulk RNA-seq data analysis, GSE276757,
3. Rat single nucleus RNA sequencing (snRNA-seq) data analysis, GSE276758 https://github.com/leeoesterreich/BRCA_Rat_YoungerOlder_snRNAseq
4. Rat whole exome sequencing (WES) data analysism, GSE276759 https://github.com/leeoesterreich/RatAgingWES
5. Human single cell RNA sequencing (scRNA-seq) of ER+ breast cancer, publically available at Wu et al. 2021. Nat. Genetics
6. Public BRCA bulk RNA-seq or microarray data analysis: we used Mutual Information Concordance Analysis (MICA), https://github.com/jianzou75/MICA
   • TCGA, METABRIC, SCAN-B

Summary of this study

• Novelty and consistency of HSD17B7 findings; not yet described as a mechanism by which age-related breast cancer may occur. Favoring action of E2 in the older TME rather than E1.
• ER and ESR1 changes with age.
• Harboring chronic inflammation in circulating environment, similar phenotype in the TME
• Macrophages as hubs of integration of the unique signals in the aged TME.