Inhibition of inflammation in adipose tissue accelerates mammary tumor development in mice

Proinflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting adipocyte inflammation, specifically in the context of mammary tumor development, through local adipocyte-specific expression of the anti-inflammatory adenoviral RIDa/ß protein complex. Suppression of adipose tissue inflammation (“RIDad mice”) in a mammary tumor model driven by MMTV-PyMT (“PyMT-RIDad mice”) led to an elevated number of tumor-associated macrophages (TAMs) in the mammary fat pad (MFP). This was accompanied by metabolic dysfunction and abnormal mammary gland development. Importantly, this phenotype correlated with accelerated mammary tumor onset, enhanced growth, and lung metastasis. Tumors in PyMT-RIDad mice exhibited upregulated CD36 expression, suggesting enhanced fatty acid uptake. Conversely, inhibition of tumor cell inflammation by RIDa/ß in ductal epithelial cells delayed mammary tumor growth but had no effect on tumor onset or macrophage accumulation. These findings highlight the differential impact on tumor development exerted through the suppression of inflammatory signals in different cell types in the microenvironment. Our results underscore the role of the suppression of adipocyte inflammation leading to a tumor-friendly microenvironment, promoting mammary cancer progression. This study sheds light on the complex interplay between inflammation specifically driven by the adipocyte in breast cancer pathogenesis. Overall design: To investigate the in vivo impact of inhibiting inflammation in adipocytes on mammary tumor development, we performed RNA-seq on both tumor tissue and mammary fat (adipocytes) to evaluate changes in mRNA expression following inflammation suppression in adipocytes using PyMT and PyMT-RIDad mice