Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice
Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer
Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer
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Research Article Inflammation Metabolism Oncology

Inhibiting inflammation in adipocytes accelerates mammary tumor development in mice

Abstract

Proinflammatory signaling in adipocytes is essential for healthy adipose expansion, remodeling, and tissue integrity. We investigated the effects of targeting inflammation in either adipocytes or mammary gland epithelial cells, in the context of mammary tumor development, by locally expressing the antiinflammatory adenoviral RIDα/β protein complex in a cell type–specific manner. Suppression of adipocyte inflammation (RIDad mice) in a mammary tumor model driven by MMTV-PyMT (PyMT-RIDad mice) led to an elevated number of tumor-associated macrophages and upregulation of immunoregulatory molecules in the mammary fat pad. 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, suppression of inflammation in mammary gland epithelial cells by RIDα/β expression (RIDMMTV mice) decelerated mammary tumor growth without affecting 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.

Authors

Dae-Seok Kim, Toshiharu Onodera, Jan-Bernd Funcke, Kyounghee Min, Qingzhang Zhu, Qian Lin, Shiuhwei Chen, Chanmin Joung, Min Kim, R. Max Wynn, Joselin Velasco, Charlotte Lee, Megan Virostek, Chao Li, Philipp E. Scherer

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Figure 4

Earlier mammary tumor onset, accelerated tumor growth, and a higher incidence of lung metastasis in PyMT-RIDad mice.

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Earlier mammary tumor onset, accelerated tumor growth, and a higher inci...
(A) Schematic representation of the generation of PyMT-RIDad mice by introducing RIDad mice into the MMTV-PyMT mammary tumor model. (B) Analysis of the mammary fat pad (MFP) in PyMT-RIDad mice revealed abnormalities in mammary gland development, as evidenced by H&E staining. Scale bars: 100 μm. Representative samples are shown. (C) Kaplan-Meier tumor-free mouse curves from 2 independent experiments. n = 13–16/group. (D and E) Tumor weight (D) and body weight (E) at the end of the experiment. n = 13–16/group. (F) Images of tumors formed in each group at the end of the experiments (mice approximately 20 weeks old). A circle indicates multiple tumors that were harvested from a single mouse. (G) Representative immunostaining of Ki67 in the tumors. n = 3/group. Scale bars: 50 μm. (H) Representative immunostaining of CD31 in the tumors. Scale bars: 50 μm. (I) Quantification of the percentage of CD163-positive area from the experiments shown in H. A total of 14–16 images from 3 mice per group were quantified. (J) H&E staining shows metastatic breast tumor development in the lungs of PyMT-RIDad mice. A magnified image of Ki67-immunostained tumor is provided. Scale bars: 100 μm. Data are displayed as mean ± SEM and were analyzed by unpaired 2-tailed t tests (D, E, and I).