Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue

Authors

• Gaofeng Xiong, University of KentuckyFollow
• Daheng He, University of KentuckyFollow
• Dana L. Napier, University of KentuckyFollow
• Jing Chen, University of KentuckyFollow
• Haizhu Shi, University of Kentucky
• Chun Li, University of Kentucky
• Paula J. Hurley, Vanderbilt University Medical Center
• Chi Wang, University of KentuckyFollow
• Haining Zhu, University of KentuckyFollow
• Changcheng Zhou, University of CaliforniaFollow
• Therese J. Bocklage, University of KentuckyFollow
• Ren Xu, University of KentuckyFollow

Abstract

Fibrosis is an important feature of adipose tissue in obese individuals; nevertheless, roles of obesity-associated extracellular matrix (ECM) deposition in breast cancer progression largely remain elusive. Here, we show that expression of Hsp47, a chaperone protein involving collagen secretion, is induced in adipose tissue from obese humans and mice. Adipocyte-specific Hsp47 deletion (Adi-KO) suppresses the high-fat diet (HFD)-induced obesity and mammary tumor progression, accompanied by a reduction in ECM deposition. Matrisome analyses lead to the identification of asporin as a new target of Hsp47 in adipose tissue. Co-immunoprecipitation results confirm that the recruitment of Hsp47 enhances asporin secretion in adipocytes. We further show that knockout of asporin suppresses HFD-induced mammary tumor growth, while exogenous of asporin partially rescues tumor growth in the decellularized mammary gland derived from Hsp47 Adi-KO mice. These results indicate that asporin at least partially mediates Hsp47 function in HFD-associated tumor progression. Digital spatial profiling (DSP) analyses show that Hsp47 depletion significantly increases the accumulation of CD8 T cells in tumor and tumor-associated adipose tissues. These results implicate that Hsp47, along with-it mediated ECM deposition, suppresses the anti-tumor immunity under HFD conditions. These findings reveal Hsp47 as a novel target for mitigating obesity-associated breast cancer progression.

Document Type

Article

Publication Date

2025

Notes/Citation Information

R E S E A R C H Open Access© The Author(s) 2025. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/

Digital Object Identifier (DOI)

https://doi.org/10.1186/s13058-025-02076-9

Funding Information

This work is supported by the National Institutes of Health (R01CA207772, R01CA277946, and R01CA274981 to R.X, 7R21AG080176-02 to G.X, 1R01CA211695-01A1 to PJH).

Repository Citation

Xiong, Gaofeng; He, Daheng; Napier, Dana L.; Chen, Jing; Shi, Haizhu; Li, Chun; Hurley, Paula J.; Wang, Chi; Zhu, Haining; Zhou, Changcheng; Bocklage, Therese J.; and Xu, Ren, "Hsp47 drives obesity-associated breast cancer progression by enhancing asporin deposition in adipose tissue" (2025). Markey Cancer Center Faculty Publications. 490.
https://uknowledge.uky.edu/markey_facpub/490