Adipocyte Hsp47: A Novel Regulator of Obesity and Obesity-Associated Breast Cancer

Baorui Kang¹, Ren Xu², Gaofeng Xiong^3*

¹Department of Veterinary Biosciences, OSU Nutrition Program, The Ohio State University, Columbus, OH 43210, USA

²Markey Cancer Center, Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA

³Department of Veterinary Biosciences, Comprehensive Cancer Center, The Ohio State University, 10.1002/hep.32181 From NLM Medline. Columbus, OH 43210, USA

Abstract

Obesity or being overweight is a growing global health concern and a significant risk factor for various cancers, including breast cancer. The increased incidence and poor adverse outcomes of breast cancer in individuals with obesity have prompted research into the molecular mechanisms linking obesity, adipose tissue remodeling, and tumor progression. Adipose tissue, which surrounds mammary tumor, is viewed not only as an energy storage and endocrine organ, but also as an active participant in breast cancer biology. Fibrosis, a key feature of obese adipose tissue, can contribute to a pro-tumorigenic macroenvironment by altering extracellular matrix (ECM) deposition, composition and alignment. Heat Shock Protein 47 (Hsp47) is a chaperone protein facilitating collagen secretion. Recent studies indicate that elevated Hsp47 expression in adipocytes is associated with obesity, sheds new light on the mechanisms underlying obesity-associated breast cancer progression. Adipocyte-expressed Hsp47 promotes obesity-associated breast cancer progression by contributing to ECM deposition and modulating immune responses within the tissue environment. It reveals a novel role of adipose tissue in breast cancer progression and has identified Hsp47 as a potential therapeutic target for obesity-associated breast cancer.

Introduction

Breast cancer becomes the most diagnosed malignancy affecting women worldwide and is a leading cause of cancer-related mortality. Obesity, affecting approximately 74% of adults in the United States¹, is now widely recognized as a major risk factor for breast cancer incidence and progression^{2, 3}. It contributes to poorer prognosis, higher recurrence rates, and increased mortality across multiple subtypes, independent of menopausal or hormone receptor status. Beyond systemic metabolic effects, obesity induces profound alterations in adipose tissue, including chronic inflammation, extracellular matrix (ECM) remodeling, and dysregulated secretion of adipokines and cytokines, thereby creating a tumor-promoting microenvironment^4-6. Considering the strong link between adipose tissue dysfunction and cancer progression, recent studies have focused on identifying molecular mediators that connect obesity-driven adipose remodeling with breast tumor biology. In this mini review, we synthesize well-established adipocyte tumor interactions and recent discovery on ECM remodeling in context of high fat-diet induced obesity and obesity-associated breast cancer progression, as well as their therapeutic relevance.

Mechanisms of Adipocyte-Tumor Crosstalk

Adipocytes are increasingly recognized as active modulators of breast cancer biology rather than passive bystanders. These cells release adipokines (like Leptin, adiponectin), pro-inflammatory cytokines (such as IL-6, IL-8, PAI-1, MCP-1, CCL2, CCL5, IL-1β, TNFα, CXCL3, CXCL8, CXCL12, etc.), and growth factors (FGFs, TGFβ, IGF, VEGF) that directly promote tumor cell proliferation, epithelial–mesenchymal transition (EMT), stemness, drug resistance, invasion and metastasis, and anti-ferroptosis^{4, 6-12}. Beyond direct promotion, adipocytes provide metabolic substrates such as free fatty acids, glycerol, glutathione, and lactate^13-17. They are actively taken up by breast cancer cells to support mitochondrial oxidative metabolism and biosynthesis, particularly under nutrient-deprived or hypoxic conditions. This metabolic link not only sustains tumor growth but also leads to treatment resistance. Additionally, adipocyte-derived extracellular vesicles participate in signaling pathways that regulate tumor and stromal cell behavior by delivery proteins or miRNAs (miR-155-5p, miR-10a-3p, miR-30a-3p), providing an additional connection within the microenvironment^18,19. Furthermore, adipocyte signals also influence immune cells in the tumor environment. They promote M2-like macrophage polarization, reduce cytotoxic T cell activity, and increase regulatory T cell recruitment, which together create an immunosuppressive environment^{20, 21}. Concurrently, the adipocyte secretome remodels extracellular matrix components, altering tissue stiffness and architecture, thereby promoting tumor dissemination and metastatic colonization. Together, these multifaceted interactions collectively underscore the pivotal role of adipocytes as dynamic participants within the breast cancer ecosystem, highlighting their potential as therapeutic targets for disrupting the obesity-cancer axis.

ECM Remodeling in Obesity and Obesity-Associated Breast Cancer

The ECM serves as both a structural scaffold and a signaling platform that regulates adipocyte function and tumor cell behavior. In obesity, adipose tissue expansion leads to excessive ECM deposition, fibrosis, and altered mechanical properties, which in turn impair adipocyte metabolism and sustain chronic inflammation. Obesity also increases collagen (such as collagen I, III and VI), fibronectin, laminin, and other ECM proteins (matrix metalloproteinases, MMPs), stiffening tissue and enhancing mechanotransduction in adipocytes and nearby epithelial cells^{5, 22}. Additionally, obesity-associated ECM remodeling promotes the accumulation of advanced glycation end products (AGEs) and triggers integrin-mediated pathways that facilitate adipose inflammation and insulin resistance⁵. These ECM alterations remodel the local microenvironment, creating conditions that promote tumor initiation, growth, and resistance to treatment⁵. In breast cancer, the crosstalk between hypertrophic adipocytes, immune cells, and ECM components has been recognized as a critical driver of tumor progression. For example, increased ECM stiffness directly activates transcription factor YAP/TAZ, NG2/EGFR and MAPK to promote breast cancer growth, migration and metastasis, increased growth factors and cytokines secretion induces angiogenesis and immune evasion²³. Therefore, understanding how obesity-associated ECM remodeling in adipose tissue influences breast cancer development is essential for identifying new therapeutic targets.

The Role of Adipocyte Hsp47 Mediated in Obesity, ECM Remodeling and Obesity-Associated Breast Cancer

The procedure of obesity associated fibrosis and ECM remodeling require precise regulation of collagen biosynthesis and secretion, processes that are critically dependent on molecular chaperones. Heat shock protein 47 (Hsp47) is a well-known collagen-specific chaperone encoded by SERPINH1 and localized in the endoplasmic reticulum. It facilitates the proper folding, secretion, and stabilization of collagen triple helices²⁴. Previous studies have demonstrated that Hsp47 is highly expressed in breast cancer cells, where it contributes to tumor progression and is identified as a hub of the ECM transcription network²⁵. Elevated Hsp47 expression has been reported in several cancers, including breast cancer, and has been associated with enhanced metastatic potential and poor prognosis^{25, 26}. Recent findings indicate that Hsp47 is enriched in adipose tissue of obese mice and humans^{27, 28}. Due to its crucial role in the secretion of collagen, a key ECM component that drives tissue stiffness and fibrosis, elevated Hsp47 expression in adipose tissue under obese conditions may enhance ECM deposition and foster a macroenvironment that supports tumor progression. Genetical deletion adipocyte Hsp47 murine model displays a suppression of high fat diet (HFD)-induced weight gain, adipocyte hypertrophy, glucose intolerance, and systemic insulin resistance²⁷. Hsp47 expression in adipose tissue is positively correlated with obesity-related parameters such as body mass index in human²⁸. Moreover, obesity-associated fibrosis in adipose tissue has been shown to promote breast cancer progression. In our study, deletion of adipocyte Hsp47 significantly inhibited tumor growth in orthotopic breast cancer models under HFD condition. Collectively, adipocyte Hsp47 is a critical regulator of both obesity development and obesity-associated cancer progression (Figure 1), positioning it as a molecular link between adipose tissue dysfunction and tumor biology.

Figure 1: A scheme showing the role of adipocyte Hsp47 in HFD-induced obesity and obesity-associated breast cancer progression.

Genetically adipocyte-specific deletion of Hsp47 reduces collagen accumulation, macrophage infiltration, and inflammation in adipose tissue, confirming its pivotal role in adipose fibrosis²⁷. A breakthrough in this study was the identification of asporin as a critical ECM protein downstream of Hsp47 in adipose tissue²⁷. Asporin, a member of the leucine-rich small proteoglycan (SLRP) family, has previously been shown to influence cell signaling, collagen organization, and inflammation, and is associated with cartilage and a variety of malignancies. However, its involvement in cancer progression is relatively underexplored. In adipose tissue, asporin expression is significantly upregulated in obese individuals and positively correlates with Hsp47 levels²⁷. The secretion of asporin in adipocytes is regulated by Hsp47²⁷. Genetic knockout of asporin prevents HFD-induced obesity and suppresses mammary tumor growth, highlighting its role in ECM-mediated breast cancer progression. Hsp47 binds to asporin via its C-terminal leucine repeat sequence-rich structural domain, thereby promoting asporin maturation and secretion in the ECM²⁷ (Figure 1). Obesity is often associated with immunosuppression, characterized by impaired cytotoxic T cell activity and chronic inflammation, both of which contribute to cancer progression^{20, 21}. ECM alterations driven by adipocyte Hsp47 and asporin may contribute to an immunosuppressive tumor environment by impeding CD8 T cell infiltration and function, especially by impairing GZMB activity, thereby promoting tumor survival and growth²⁷. Collectively, this study establishes asporin as a novel downstream ECM effector of adipocyte Hsp47, which provides new insights into the mechanisms by which asporin contributes to tumor progression.

Therapeutic Implications and Future Directions

Given the interaction between adipocyte and breast cancer during tumor progression and treatment resistance, targeting adipocytes or metabolic secretome may enhance therapy efficacy. However, clinical use of metformin, an FDA-approved drug for type II diabetes, has not improved progression-free survival in breast cancer patients, underscoring the need for more effective strategies²⁹. The GLP-1 receptor agonists (GLP-1RAs), recently used in type 2 diabetes treatment and weight loss, does not increase the risk of breast cancer, more research is needed to understand safety and its benefit for breast cancer patients with obesity^{30, 31}. The small molecule Hsp47 inhibitor Col003, which prevents HFD-induced body weight gain, reduces obesity-associated fibrosis and aspirin deposition, and slows tumor growth²⁷. This positions Hsp47 as a novel and promising therapeutic target, especially in the context of obesity-associated breast cancer. Previous reports have shown that cancer cell-expressed Hsp47 promotes breast cancer growth, invasion and metastasis by enhancing tumor collagen deposition and driving EMT^{25, 26}. In the current study, it is demonstrated that adipocyte-expressed Hsp47 contributes to obesity development, ECM remodeling, fibrosis, and modulation of tumor-infiltrating T cells within the tumor microenvironment, synergistically promoting breast cancer progression²⁷. Therefore, therapeutically targeting Hsp47 may offer a comprehensive approach to simultaneously target both cancer cells-intrinsic mechanisms and supportive tumor microenvironment and macroenvironment interactions. While clinical trials targeting Hsp47, such as siRNA targeting BMS-986263, are currently underway for fibrosis disease³², similar approaches have not yet been explored in breast cancer patients. Investigating Hsp47 targeting, such as with BMS-986263 in breast cancer, is a promising avenue worth pursuing.

Conclusion

In conclusion, the study demonstrates that adipocyte Hsp47 contributes to ECM remodeling, adipose tissue fibrosis, and immunosuppression by promoting secretion and deposition of asporin in adipose tissue. The findings provide a mechanistic explanation for the increased risk of breast cancer observed in obese women. Be regulating ECM composition, partially through asporin, adipocyte Hsp47 helps establish a tumor supportive environment that suppresses anti-tumor immunity. Therefore, targeting Hsp47 emerges as a promising therapeutic strategy for both inhibiting obesity and mitigating the progression of obesity-associated breast cancer. Considering the high prevalence of obesity in women and its association with poor breast cancer outcomes, the development of specific Hsp47 inhibitors holds promising potential for both the prevention and treatment of obesity-associated breast cancer.

Acknowledgment

This work was supported by grants from NIH (grant number 7R21AG080176) and the start-up funding from The OSU Comprehensive Cancer Center to G.X.

Conflict of Interest

There are no conflicts of interest to report.

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