New Insights Into Adipokines and the Tumor Microenvironment in Breast Cancer

Abstract

Breast cancer remains the malignant tumor with the highest incidence among female patients globally, and its treatment represents a well-recognized clinical challenge. Recent studies have demonstrated that the tumor microenvironment (TME) exerts a substantial influence on breast cancer progression, whereby alterations in its internal molecular components ultimately impact disease outcomes. Key factors implicated in this process include adipokines and microRNAs (miRNAs). This review provides a detailed description of how different adipocytokines exert specific mechanistic effects on breast cancer cells. By integrating adipokines with miRNAs, the discussion explores their combined roles in the initiation and progression of breast cancer, addressing a previously unaddressed research gap in studies focusing solely on individual adipokines. Furthermore, by examining the interactions between miRNAs and signaling pathways, this analysis offers a holistic perspective on the TME network, thereby fostering new therapeutic insights for breast cancer management.

Introduction

Breast cancer poses a significant threat to women’s health globally, having become the most commonly diagnosed cancer among females worldwide. According to data from the International Agency for Research on Cancer (IARC), there were 2.26 million new cases in 2020, representing 24.5% of all malignant tumors diagnosed in women. ¹ In China, there are about 420000 new cases every year, and over 120000 women die as a result. ² This not only threatens patients’ lives and induces psychological trauma but also imposes substantial economic burdens on families, with treatment costs frequently overburdening low- and middle-income households.

The TME exerts a profound influence on the progression of breast cancer. It is composed of various cellular components and the extracellular matrix, which provides the conditions necessary for the growth, proliferation, and metastasis of tumor cells. ³ Adipocytokines, which are bioactive molecules secreted by adipose tissue, such as leptin and adiponectin, are expressed in the TME and interact with each other to regulate the progression of breast cancer. Adipose tissue also influences the development of breast cancer through the secretion of miRNAs, the regulation of metabolic pathways, and the interaction between adipose-derived stem cells (ASCs) and cancer cells.

A thorough exploration of the relationship between adipocytokines and the TME is of great significance. On the one hand, it facilitates the discovery of novel therapeutic targets and the development of more effective therapeutic agents. Currently, conventional treatments for breast cancer are beset with limitations such as drug resistance and side effects. Conversely, targeted therapeutic drugs that act on leptin and its receptors have demonstrated promising progress in clinical trials. ⁴ The regulatory effects of certain adipokines on angiogenesis and the infiltration of immune cells within the TME also offer novel perspectives for anti-angiogenesis therapy and immunotherapy. ⁵ On the other hand, it has the potential to innovate the diagnostic and treatment modalities of breast cancer. Traditional diagnostic approaches encounter challenges in terms of early detection, often accompanied by a high rate of misdiagnosis. Adipocytokines, as novel biomarkers, are readily detectable with high sensitivity. A decrease in the serum adiponectin level is closely associated with the onset and progression of breast cancer, and adiponectin shows promise for application in early diagnosis and prognosis assessment. ⁶ Meanwhile, monitoring the changes in adipokine levels can provide a foundation for personalized treatment. Based on the research findings regarding the interaction mechanism between adipokines and the TME, more precise treatment plans can be formulated. These plans have the potential to enhance the efficacy of treatment and reduce side effects. Therefore, the research on adipokines and the TME represents an important area of exploration in the current medical field, offering new hope for combating breast cancer.

Definition and Function of Adipocytokines

Adipokines, as a group of bioactive molecules secreted by adipocytes, play a pivotal regulatory role in the biological behavior of tumor cells and the shaping of the tumor microenvironment. There exists a diverse range of adipokines, each with distinct functions. For instance, leptin and resistin are known to promote tumor growth, invasion, and metastasis, whereas adiponectin inhibits tumor progression and exerts anti-tumor effects. These adipokines interact with other constituents within the tumor microenvironment, forming a complex network that collectively influences the development of breast cancer.

Leptin

Leptin, which is mainly secreted by white adipose tissue, binds to and activates its homologous receptor, the leptin receptor (LEP - R). Through the negative feedback regulation mechanism between adipose tissue and the hypothalamus, it regulates appetite and energy expenditure, thereby maintaining energy balance. ⁷ When the body’s fat content increases, leptin secretion rises and acts on the hypothalamus. This has a significant impact on reducing food intake and increasing energy expenditure, thereby promoting fat breakdown. On the contrary, when the body is in a state of hunger or energy deficiency, leptin secretion declines, appetite increases, and energy expenditure decreases to conserve the body’s energy. ⁸

In the occurrence and development of breast cancer, leptin plays a pro - cancer role. It can activate multiple tumor - related signaling pathways, such as the Janus kinase - signal transduction and transcriptional activator (JAK2 - STAT3) pathway and the phosphatidylinositol 3 - kinase (PI3K) pathway, etc. ⁹ On the one hand, after leptin binds to the leptin receptor on the surface of breast cancer cells, the JAK2 - STAT3 pathway is activated. The receptor - related JAK is activated and undergoes mutual phosphorylation, phosphorylating the intracellular tail of its receptor. This directly creates docking sites for STAT, leading to their binding to DNA and the activation of target genes, thereby regulating the expression of a series of genes related to cell proliferation and survival and promoting tumor cell proliferation. ¹⁰ Studies have demonstrated that in breast cancer cell lines, exogenous leptin can remarkably enhance cell proliferation in a dose-dependent fashion. ¹¹ On the other hand, leptin activates the PI3K pathway, promotes the phosphorylation of Akt protein, and thereby facilitates the proliferation and migration of tumor cells. ¹² In addition, leptin is capable of inducing tumor angiogenesis, thereby providing adequate nutritional support for the growth and metastasis of tumors ¹³ ; It can also modulate the function of immune cells within the tumor microenvironment. It induces the polarization of M2 macrophages and stimulates the migration and invasion of breast cancer cells via multiple cellular signaling pathways. ¹⁴

Adiponectin

Adiponectin, which is also derived from adipose tissue, has a strikingly different function from leptin and predominantly plays an anti-tumor role. It is translated and modified from a 30 kDa monomeric protein into various oligomers (low molecular weight or trimer, medium molecular weight or hexamer, and high molecular weight) and then secreted into the circulatory system. By binding to adiponectin receptor 1 (AdipoR1) and adiponectin receptor 2 (AdipoR2) on the surface of target cells, it initiates a series of tissue-dependent signal transduction events and exerts its biological functions. ¹⁵

Adiponectin possesses potent anti - inflammatory, anti - atherosclerotic, and insulin - sensitizing effects. ¹⁶ In the realm of breast cancer research, adiponectin can inhibit the proliferation, migration, and invasion of tumor cells. Upon binding to receptors such as AdipoR1, AdipoR2, and T-cadherin, adiponectin activates the leptin and insulin signaling pathways in the hypothalamus. This activation leads to the regulation of glucose and lipid metabolism, thereby enhancing the binding of energy homeostasis receptors. Simultaneously, upon activating the downstream AMPK signaling pathway, adiponectin inhibits the MAPK, PI3K/AKT, WNT-β-Catenin, NF-κB, and JAK2-STAT3 pathways, effectively suppressing the growth of tumor cells. Paradoxically, in estrogen receptor-positive (ER+) breast cancer, adiponectin has been found to promote the proliferation of tumor cells. ¹⁷ Studies have demonstrated that in breast cancer cells, treatment with adiponectin significantly reduces cell proliferation rates, induces cell cycle arrest, promotes apoptosis, and inhibits tumor angiogenesis. By downregulating the expression of angiogenic factors such as vascular endothelial growth factor (VEGF), adiponectin reduces the formation of tumor neovascularization. This thereby limits the nutritional supply to tumors, inhibiting their growth and metastasis. ¹⁸ With regard to tumor immune regulation, adiponectin can induce the polarization of macrophages towards the M1 phenotype, ¹⁹ M1 macrophages secrete a substantial amount of pro-inflammatory cytokines, including interleukin-6 (IL-6), interleukin-12 (IL-12), interleukin-23 (IL-23), and tumor necrosis factor-alpha (TNF-α). These cytokines inhibit cell proliferation, induce tissue damage, activate immune cells, kill tumor cells, and promote antigen presentation. By doing so, they facilitate the further recruitment of immune cells and signal transduction in anti-tumor pathways, thereby enhancing the anti-tumor activity of immune cells. As key tumor-suppressive cells, M1 macrophages function within the TME to inhibit tumor cell growth. ²⁰

Resistin

Resistin, a polypeptide hormone secreted by adipocytes, is crucial in the pathogenesis of obesity, insulin resistance, and type 2 diabetes. It contains a cysteine-rich protein motif, which is responsible for forming disulfide bonds and facilitating the assembly of hexamers. Hexamers constitute the predominant form of resistin in mouse serum, with a minor fraction existing as trimers. These oligomers are induced during adipogenesis, the process of adipocyte differentiation. ²¹

In breast cancer, resistin-stimulated adipose-derived stem cells (ADSCs) can augment the malignant phenotype of breast cancer cells, thereby exhibiting potent pro-tumor activity. ²² In prostate cancer, resistin can regulate the expression of matrix metalloproteinases (MMPs), such as MMP-2 and MMP-9. These enzymes degrade extracellular matrix components like collagen and fibronectin, thereby reshaping the extracellular matrix and facilitating the migration and invasion of tumor cells. However, the role of resistin in breast cancer remains to be explored. ²³ The interaction between resistin and adenylate cyclase-associated protein 1 (CAP1) increases intracellular cyclic adenosine monophosphate (cAMP) levels, augments protein kinase A (PKA) activity, and activates the nuclear factor-κB (NF-κB) signaling pathway. This cascade regulates the expression of genes involved in inflammation and cell proliferation. Through the overexpression and activation of STAT3, it promotes breast cancer cell growth, invasion, and the acquisition of stem cell-like characteristics. ²⁴ In addition, resistin levels in the serum of breast cancer patients are often significantly elevated and closely correlated with inflammatory markers, cancer stage, tumor size, metastasis, and prognosis. Resistin serves as a biomarker for breast cancer, reflecting advanced disease stage and inflammatory status. ²⁵

Chemerin

Chemerin, a recently discovered adipokine, is primarily secreted by white adipose tissue and the liver, playing a role in inflammation, adipogenesis, angiogenesis, and energy metabolism. Encoded by the retinoic acid receptor-responsive gene 2 (Rarres2), also known as tazarotene-induced gene 2 (TIG2), chemerin mediates diverse physiological and pathological processes by binding to the chemokine receptor ChemR23. ²⁶

Chemerin acts as an efficient macrophage chemotactic protein, promoting macrophage adhesion to vascular cell adhesion molecule-1 (VCAM-1) and fibronectin by aggregating very late antigen-4 (VLA-4) and very late antigen-5 (VLA-5), thereby facilitating inflammatory responses. ²⁷ In breast cancer, the role of chemerin in regulating the TME and its potential to promote tumor proliferation and metastasis remain controversial, with conflicting findings reported in the literature. Studies have shown that chemerin expression is significantly elevated in breast cancer tissues compared to normal tissues, and is negatively correlated with patient prognosis. Higher chemerin expression has been associated with reduced patient survival rates, increased recurrence risk, and shorter survival periods. Importantly, chemerin expression levels represent an independent factor influencing 5-year disease-free survival. ²⁸

Visfatin

Visfatin, also known as pre-B cell colony-enhancing factor (PBEF), is a multifunctional adipocytokine primarily secreted by inflammatory cells and adipocytes in adipose tissue. Acting on multiple target tissues through complex biological pathways, visfatin is also expressed in extra-adipose tissues, where it mediates inflammatory responses and exhibits chemotactic, pro-angiogenic, pro-fibrotic, and pro-proliferative activities. ²⁹

During breast cancer research, numerous studies have indicated that visfatin exhibits pro-tumor properties. Visfatin induces de novo lipid synthesis in MCF-7 cells via the EGFR/PI3K/AKT/GSK3β pathway, thereby enhancing the survival and proliferation of breast cancer cells. ³⁰ Visfatin can upregulate VEGF expression, elevating circulating VEGF levels to stimulate angiogenesis in the tumor microenvironment. This process enriches tumor microenvironmental nutrients and oxygen supply, thereby promoting an increase in cancer stem cell (CSC) populations. ³¹ Visfatin can induce the secretion of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α), inhibit apoptosis of neutrophils and macrophages, promote the release of MMPs and chemokines, and facilitate epithelial-mesenchymal transition (EMT), thereby playing a pivotal role in shaping the TME. ³² In breast cancer patients, serum visfatin levels are often elevated and closely correlated with tumor malignancy, size, metastasis, and patient survival. It has emerged as a potential biomarker for assessing disease status and prognosis. ³³

Osteopontin

Osteopontin is a multifunctional phosphorylated glycoprotein secreted by diverse cell types, including osteoclasts, osteoblasts, neurons, inflammatory cells, and tumor cells. ³⁴ Osteopontin is widely involved in biological processes such as cell adhesion, migration, proliferation, and immune regulation, and plays a critical role in tumor initiation and progression.

In the breast cancer TME, osteopontin maintains cancer cell proliferation signals by regulating signaling pathways such as Akt and Raf/MEK/ERK. It supports anchorage-independent growth by inducing oxidoreductase expression, protecting cells from death during this process. Osteopontin also activates the STAT1 and STAT3 signaling pathways, increasing glucose levels in breast cancer cells to fuel tumor cell growth. Additionally, it induces the expression of cell surface receptors like integrins and CD44, enhances Met kinase activity, and promotes cancer cell migration and invasion. ³⁵ Research has found that, ³⁶ in tumor cells, osteopontin binds to α4β1 integrin and exhibits chemokine-like functions, attracting immunosuppressive cells such as tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) to accumulate around tumors. Additionally, osteopontin activates the JNK/c-jun signaling pathway by binding to the novel receptor LYVE-1, promoting the proliferation of highly immunosuppressive tissue-resident tumor-associated macrophages (TRM-TAMs). This enables cancer cells to evade immune system surveillance and attack. Clinical studies have shown that osteopontin expression levels in breast cancer tissues are closely correlated with tumor stage, lymph node metastasis, and patient prognosis. Patients with high osteopontin expression exhibit poor prognosis and increased recurrence risk. ³⁷

Apelin

Apelin, mainly secreted by adipocytes, is known as the ligand for G-protein-coupled receptor APJ and binds to angiotensin II type 1 receptor-related protein (APJ). It is involved in various physiological processes, including cardiovascular regulation, nervous system function, and metabolic homeostasis. ³⁸

In breast cancer research, Apelin has emerged as a molecule with a complex role. It can enhance tumor cell proliferation and survival, driving the growth of MCF-7 cells through the ERK1/2/AIB1 signaling pathway. This process increases cyclin D1 expression, accelerates the cell cycle, and promotes tumor cell growth. ³⁹ On the other hand, Apelin can also participate in the regulation of tumor angiogenesis. It can stimulate endothelial cell proliferation, promote the construction of tumor neovascularization, and provide nutritional support for tumor development. Moreover, the Apelin/Apelin receptor pathway does not overlap with VEGFR signaling pathway, and both have independent roles in angiogenesis. ⁴⁰ In recent years, significant advancements have been made in understanding the molecular mechanisms of the Apelin receptor, particularly in the dynamic regulation of G protein-coupled receptor (GPCR) dimerization and signaling pathways. This research offers novel therapeutic targets for the treatment of breast cancer and other diseases. ⁴¹ However, the precise role of Apelin in breast cancer remains to be fully elucidated, including its effects on the TME and synergistic interactions with other targets (such as GLP-1R). Future research may enable the development of precise therapeutic interventions through antibody-drug design.

Lipocalin-2

Lipocalin-2, a secreted protein of the lipocalin family, is present in diverse cell types such as adipocytes and macrophages, participating in lipid metabolism, inflammatory responses, and immune regulation. ⁴²

Lipocalin-2 promotes breast tumor initiation and progression by exerting pro-tumor effects. It forms a complex with MMP-9, thereby enhancing tumor cell invasion and metastasis. Lipocalin-2 upregulates MMP-9 expression and activity, enabling tumor cells to degrade extracellular matrix components like collagen. This facilitates their penetration of the basement membrane and infiltration into surrounding tissues. ⁴³ Lipocalin-2 induces EMT in breast cancer cells, causing epithelial cells to lose polarity and intercellular junctions, acquire mesenchymal characteristics, and enhance their migratory and invasive capacities. In TNBC cells, CRISPR-mediated knockout of Lipocalin-2 significantly reduces cell invasion, with its mechanism potentially involving the ER/Slug signaling pathway. ⁴⁴ Lipocalin-2 exhibits heterogeneous expression in breast cancer cells, with tumors showing high Lipocalin-2 expression demonstrating faster growth and increased angiogenesis. HER2 regulates Lipocalin-2 expression via the HER2/AKT/NF-κB signaling pathway, thereby promoting tumorigenesis. Additionally, Lipocalin-2 upregulates HIF-1α expression through the Erk pathway, increasing VEGF levels and stimulating angiogenesis. ⁴⁵ In addition, Lipocalin-2 is associated with tumor cell drug resistance, as its expression can predict tumor cell sensitivity to chemotherapy. This association poses new challenges and research directions for the clinical treatment of breast cancer. ⁴⁶

Tumor Microenvironment

Definition and Components of the TME

The TME is a crucial site for the survival of tumor cells. It is composed of various active components, including cells, the extracellular matrix, and cytokines. ³ It is interdependent with tumor cells and mutually influences them, playing a pivotal regulatory role in the initiation, progression, infiltration, metastasis, and treatment of tumors. ⁴⁷ The major components of the TME are diverse immune cells, including T cells, B cells, macrophages, and NK cells. These immune cells continuously monitor the tissue and are tasked with identifying and eliminating tumor-prone cells and other abnormal cells. Nevertheless, tumor cells manage to evade the killing effect of immune cells through mechanisms such as immune escape.^48,49 TAMs constitute a substantial population of immune cells within the TME. These cells have the ability to polarize into two distinct phenotypes: M1 (pro-inflammatory and anti-tumor) and M2 (anti-inflammatory and pro-tumor). During the advancement of tumors, TAMs exhibit a tendency to polarize towards the M2 phenotype, thereby facilitating the proliferation, migration, and angiogenesis of tumor cells. ⁵⁰ Fibroblasts are also a crucial component of the TME. They secrete extracellular matrix components such as collagen and fibrin. These matrix components not only offer physical support to tumor cells but also play a role in regulating their metabolism and signal transduction. Moreover, they serve as an essential pathway for tumor cell invasion and metastasis. ⁵¹ In addition, various cytokines within the TME, including growth factors and chemokines, are capable of transmitting diverse signals between cells. For instance, substances such as IL and TNF are involved in regulating the functions of immune cells and inflammatory responses. Factors like the epidermal growth factor and vascular endothelial growth factor stimulate the proliferation of endothelial cells within tumors, leading to the formation of a substantial number of new capillaries. These capillaries supply nutrients and oxygen to the tumor mass and, simultaneously, provide pathways for tumor metastasis. ⁵²

Influence of the TME on Breast Cancer Progress

The TME is intricately regulated and facilitates tumor invasion and metastasis via a variety of cellular bioactive factors.

Growth Factors and Cytokines in the TME Accelerate the Proliferation of Tumor Cells

Growth factors, including epidermal growth factor (EGF) and fibroblast growth factor (FGF), are able to bind to their corresponding receptors on the surface of breast cancer cells. This binding event activates intracellular signaling pathways such as the MAPK and PI3K pathways. Consequently, it accelerates the cell cycle progression and promotes the rapid proliferation of tumor cells.^53,54 Cytokines, including TNF-α and IL-6, not only directly stimulate the growth of tumor cells but also induce tumor cells to secrete additional growth factors via paracrine or autocrine pathways. This process establishes a feedback loop, which, rather than being a combination of positive and negative feedback as stated inaccurately before, can either be a positive feedback loop that promotes tumor cell proliferation. In fact, the typical scenario here often involves positive feedback mechanisms where the secreted growth factors further enhance tumor cell growth and proliferation.^55,56 In clinical trials, targeted blockade of the IL-6 signaling pathway significantly inhibits the proliferation rate of tumor cells and decreases the growth rate of tumors. ⁵⁷

Extracellular Matrix Remodeling in the TME Provides a Faster Pathway for Tumor Cell Invasion and Metastasis

MMPs, which serve as pivotal enzymes in the degradation of the extracellular matrix, are frequently found to be highly expressed within the TME. ⁵⁸ Cancer-associated fibroblasts (CAFs), tumor-infiltrating macrophages, and other cells are capable of secreting substantial quantities of MMPs, such as MMP-2 and MMP-9. These enzymes have the ability to degrade components of the extracellular matrix (ECM), including collagen and fibronectin. By breaking down the physical barriers of the matrix, they facilitate tumor cells in breaching the constraints imposed by the matrix and infiltrating the surrounding tissues. ⁵⁹ Meanwhile, the bioactive fragments released from the degraded matrix components, such as the products of collagen degradation, can further enhance the migration and proliferation of tumor cells. Research has revealed that the expression and activity levels of MMP-9 in breast cancer tissue are significantly correlated with breast cancer metastasis and the malignancy of the tumor. Patients with a high expression of MMP-9 typically exhibit a poor prognosis. ⁶⁰

The Immunosuppressive Milieu Within the TME Renders Tumor Cells More Prone to Immune Evasion

As previously mentioned, tumor cells establish an immunosuppressive microenvironment through inducing the expression of immune checkpoint molecules, secreting inhibitory cytokines, and regulating the metabolism of immune cells. This renders it challenging for the body’s immune system to effectively identify and eliminate tumor cells. Once tumor-associated macrophages polarize towards the M2 phenotype, they not only fail to exert anti-tumor effects but also suppress the functions of immune cells, such as T cells and NK cells, by secreting inhibitory cytokines like IL-10 and TGF-β. Simultaneously, they promote tumor angiogenesis, thereby providing favorable conditions for the growth and metastasis of tumor cells. ²⁰ The infiltration of regulatory T cells (Tregs) is elevated in the TME. These cells secrete inhibitory cytokines, such as IL-35 and TGF-β. Such cytokines inhibit the activation and proliferation of effector T cells, thereby weakening the body’s anti-tumor immune response. Consequently, this enables tumor cells to evade the surveillance of the immune system and facilitates their growth and metastasis. ⁶¹

Angiogenesis in the TME Plays an Important Role in the Progression of Breast Cancer

As tumor cells proliferate, a hypoxic environment progressively develops within the tumor tissue. Transcription factors, such as HIF, are then activated, which in turn upregulates the expression of angiogenic factors, including VEGF. ⁶² VEGF can stimulate the proliferation, migration, differentiation, angiogenesis, and regulation of permeability in endothelial cells (ECs), thereby promoting the formation of tumor neovascularization. ⁶³ These newly formed blood vessels not only supply tumor cells with an adequate amount of oxygen and nutrients to satisfy their rapid growth requirements but also offer convenient routes for tumor cells to enter the circulatory system and effectuate distant metastasis. In the clinical treatment of breast cancer, anti-angiogenic drugs such as bevacizumab have emerged as an important therapeutic strategy. These drugs can, to a certain extent, inhibit tumor growth and metastasis by specifically targeting and inhibiting the activation of the VEGF signaling pathway, which promotes angiogenesis, and by blocking tumor neovascularization. ⁶⁴

Interactions Between Adipocytokines and the TME in Breast Cancer

Adipose Cytokines can Reshape the Extracellular Matrix in the TME

Adipokines play a pivotal role in the remodeling of the extracellular matrix within the TME. There exists a diverse array of adipokines, each exerting an influence on the structure and function of the extracellular matrix via distinct molecular mechanisms. For instance, leptin, as a significant adipokine, is capable of binding to receptors on the surface of tumor cells and cancer-associated fibroblasts. This binding event activates downstream signaling pathways and induces an increase in the expression and secretion of MMPs. ⁶⁵ MMPs can effectively degrade the major components of the extracellular matrix, including collagen and fibronectin. By doing so, they disrupt the stable structure of the extracellular matrix, facilitating cancer cells in breaching the basement membrane and infiltrating and metastasizing to the surrounding tissues. ⁵⁹ Adiponectin demonstrates a more intricate mechanism of action. In certain instances, it is capable of inhibiting the secretion of MMPs by tumor cells through regulating intracellular signaling pathways. Consequently, this action preserves the integrity of the extracellular matrix ⁶⁶ ; Under other circumstances, adiponectin may facilitate the synthesis and secretion of extracellular matrix components by fibroblasts, thereby altering the composition and physical characteristics of the extracellular matrix. ⁶⁷ Resistin is also implicated in the process, as it has the ability to activate signaling pathways such as the JAK/STAT and PI3K/AKT pathways. By releasing cytokines, resistin enhances the inflammatory response within the TME. Consequently, this affects cell growth and angiogenesis in the TME, while simultaneously inhibiting the body’s anti-tumor immune response. As a result, it indirectly promotes the occurrence and progression of tumor metastasis. ⁶⁸ Other adipokines, such as visfatin and osteopontin, also contribute to the remodeling of the extracellular matrix in diverse manners. They either regulate cell adhesion or influence the metabolic equilibrium of the extracellular matrix. Ultimately, these actions collectively drive the evolution of the TME towards a state that is conducive to tumor progression. ⁶⁹

Adipose Cytokines can also Regulate Immune Cell Function in the TME

Leptin has the ability to promote the polarization of TAMs towards the M2 phenotype, thereby enhancing their anti-inflammatory and tumor-promoting properties. These polarized macrophages secrete immunosuppressive cytokines, such as IL-10, which suppresses the activity of immune cells, including T cells and NK cells. As a result, an immunosuppressive environment that is favorable for the growth of tumor cells is created. ⁷⁰ Adiponectin exerts a balancing effect in immune regulation. It inhibits inflammatory responses within the TME and suppresses tumor proliferation, growth, survival, invasion, and metastasis via diverse cellular signaling pathways. ⁷¹ Moreover, adipokines can directly or indirectly induce tumor-associated inflammation. They decrease the infiltration of Th1 cells, CD8 + T cells, NK cells, and Tregs, while promoting the infiltration of Th2 cells, M2/TAMs and CAFs. Additionally, adipokines stimulate the secretion of other tumor-promoting and immunosuppressive cytokines. In this way, an immunosuppressive microenvironment is formed, which enhances tumorigenesis, the motility of cancer cells, EMT, and angiogenesis. This, in turn, induces tumor-associated inflammation, as well as the proliferation, survival, progression, immune evasion, migration, invasion, and metastasis of cancer cells. ⁵²

TME can also Feedback and Regulate the Secretion of Adipocyte Cytokines

Growth factors, cytokines, and microenvironmental factors like hypoxia secreted by tumor cells can all influence the function of adipocytes and the expression of adipokines. The TME is typically in a hypoxic state. Tumor cells upregulate the production of HIF to adapt to this hypoxic environment. This upregulation promotes the induction of multiple gene targets, leading adipocytes to secrete more tumor-promoting adipokines, such as leptin and its receptor. ⁷² Concurrently, the hypoxic environment suppresses the secretion of adipokines that possess anti-tumor effects, such as adiponectin, ⁷³ this creates a vicious cycle that facilitates tumor progression. TAMs undergo polarization and transform into different subgroups within the tumor microenvironment. Among them, lipid-associated macrophages (LAMs) are capable of enriching lipid metabolism and exhibiting M2-like immunosuppressive effects. ⁷⁴ Subpopulations of tumor-associated macrophages express CCL2 and CCL5 within the tumor adipose microenvironment, manifesting immunosuppressive phenotypes. Simultaneously, miRNA-155, an extracellular vesicle-derived molecule that interferes with tumor adipocytes, comprehensively remodels adipocytes in the adipose microenvironment, leading to the polarization of TAMs towards the M2 phenotype. ⁷⁵ In conclusion, the TME modulates lipid metabolism and the secretion of adipokines, delicately orchestrating the interaction between the TME and adipokines.

Role of Adipocytokines in Breast Cancer Development and Progress

Adipose Tissue-Derived miRNAs in Breast Cancer Pathogenesis

Adipose tissue, a key regulator of energy metabolism, is closely intertwined with breast cancer development through the secretion of adipocytokines and release of miRNAs, forming a complex and sophisticated regulatory network.

MiRNAs, a class of endogenous non-coding small RNAs typically ∼22 nucleotides in length, possess immense regulatory potential despite their brevity. They modulate gene expression post-transcriptionally by incompletely pairing with the 3′-untranslated region (3′UTR) of target mRNAs, either inhibiting translation or inducing mRNA cleavage. This precise regulatory mechanism influences diverse biological processes, including cell proliferation, differentiation, apoptosis, and metabolism. ⁷⁶

In the breast cancer microenvironment, adipose tissue-derived miRNAs are involved in complex biological processes. For instance, miR-155, a miRNA overexpressed in multiple human malignancies, exhibits aberrant overexpression in breast cancer cells. It targets the SOCS1 gene, a negative regulator of cytokine signaling that normally suppresses tumor cell growth pathways. By binding to SOCS1 mRNA, miR-155 downregulates SOCS1 expression, constitutively activating the JAK-STAT signaling pathway in tumor cells. This drives cell proliferation, colony formation, and xenograft tumor growth. Additionally, miR-155 sustains STAT3 activation, promoting cell survival, transformation, and tumor progression. ⁷⁷ The study revealed that miR-155 overexpression in breast cancer tissue correlates with clinical stage, lymph node metastasis, a higher proliferation index (Ki-67 > 10%), and hormone receptor status in patients, indicating a poor prognosis for breast cancer patients. ⁷⁸

MiR-21 is also pivotal in the crosstalk between adipose tissue and breast cancer. It is overexpressed in breast cancer, targeting the PTEN gene in cancer cells. As a key tumor suppressor, PTEN encodes a phosphatase that antagonizes the PI3K-Akt signaling pathway, thereby inhibiting cell growth, proliferation, and migration.^79,80 In TNBC, miR-21 targets and inhibits PTEN expression, diminishing the tumor suppressor’s negative regulation of the PI3K-Akt signaling pathway. This process thereby promotes cancer cell proliferation, invasion, and metastasis, establishing a close negative regulatory relationship between miR-21 and PTEN during tumor development. Clinical studies have demonstrated that miR-21 levels are significantly elevated in the blood of breast cancer patients, with high miR-21 expression correlating with poor progression-free survival. As such, miR-21 serves as a potential biomarker for assessing disease progression and prognosis, where increased expression is often indicative of poor patient survival outcomes. ⁸¹

In addition, other miRNAs expressed in adipose tissue, such as miR-143, miR-145, also play an important role in the occurrence and development of breast cancer. Yang et al ⁸² found in mouse experiments that miR-143 can inhibit the growth of breast tumors, and Chen et al ⁸³ found in colon tumors that miR-143 can inhibit the progress of colon tumors by targeting KRAS gene. Studies have identified KRAS as a potential target in breast cancer, prompting exploration of whether miR-143 inhibits breast cancer cell proliferation and migration by targeting the KRAS gene. Additionally, miR-145 negatively regulates oncogenic pathways, suppressing cancer cell proliferation, migration, and tumor angiogenesis. Its expression levels correlate with breast cancer progression, indicating a critical inhibitory role in tumor initiation and development. ⁸⁴ These miRNAs, in conjunction with adipocytokines and other components of the TME, form a multi-level, multi-dimensional regulatory network that profoundly influences the progression of breast cancer. Further elucidation of the molecular mechanisms by which adipose tissue modulates breast cancer through miRNAs is expected to pave the way for innovative strategies in early diagnosis, prognostic assessment, and targeted therapy.

Adipose Tissue Affects Breast Cancer by Promoting Multiple Metabolic Pathways

Adipose tissue is deeply involved in breast tumor initiation and progression by secreting adipocytokines and regulating multiple metabolic pathways, creating a unique microenvironment that supports tumor cell growth, proliferation, and metastasis.

Adipose tissue’s regulation of glucose metabolism is closely linked to breast tumor progression. In obesity and other metabolic disorders, adipose tissue increases the secretion of adipocytokines such as resistin and visfatin, which disrupt the insulin signaling pathway and induce insulin resistance. ⁸⁵ Insulin resistance impairs cellular sensitivity to insulin, disrupting glucose uptake and utilization while elevating blood glucose levels. Tumor cells exhibit distinct metabolic features, preferentially utilizing aerobic glycolysis—a phenomenon known as the Warburg effect—even under aerobic conditions. This metabolic reprogramming enables them to consume large quantities of glucose, converting it into lactate to fuel their rapid proliferation. ⁸⁶ Adipose tissue-mediated insulin resistance further exacerbates glucose availability in the TME, potentially enhancing the Warburg effect in tumor cells and promoting their proliferation, as demonstrated in the study by Lettner et al, ⁸⁷ Analysis of 188 patients revealed that higher BMI correlated with increased tumor glucose uptake in breast cancer, indicating that obese individuals with breast cancer exhibit elevated glucose utilization in tumor tissue—a finding reflecting the association between obesity and tumor glucose metabolism in this population. Among breast cancer patients with obesity or insulin resistance, tumor tissue glucose uptake was significantly higher than in normal-weight counterparts, correlating with more rapid tumor growth and significantly poorer prognosis.

Adipose tissue metabolic alterations also exert a profound influence on breast cancer. Obesity-related factors drive metabolic reprogramming in both breast cancer cells and the TME, with metabolic dysfunction serving as a defining characteristic of obesity-associated breast cancer. ⁸⁸ Adipose tissue secretes hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL), which catalyze the hydrolysis of triglycerides (TAG) into diglycerides (DAG). This process releases free fatty acids (FFA) into the plasma, which subsequently enter the TME. ⁸⁹ Obesity-associated dysfunctional adipose tissue releases an increased supply of fatty acids, which breast cancer cells efficiently acquire and utilize. These fatty acids serve as energy substrates for mitochondrial β-oxidation and as building blocks for tumor cell membrane synthesis, thereby supporting tumor cell growth and proliferation. ⁹⁰ Additionally, adipocytokines such as leptin and adiponectin—previously discussed—play key roles in lipid metabolism regulation. Leptin promotes fat mobilization by enhancing appetite and energy expenditure, while adiponectin activates the AMPK pathway. This leads to inhibition of enzymes such as ACC1 and HMG-CoA, thereby reducing fatty acid and cholesterol synthesis to regulate lipid homeostasis. Dysregulated expression of both cytokines influences breast tumor initiation, progression, and patient prognosis. ⁹¹

Amino acid metabolism represents a critical interface for crosstalk between adipose tissue and breast cancer. Tumor cells exhibit a heightened demand for amino acids, particularly glutamine, which serves dual roles in supporting their malignant phenotype. As a key nitrogen donor, glutamine provides substrates for nucleotide synthesis and activates the mTOR signaling pathway to drive rapid proliferation. Additionally, it maintains intracellular redox balance by replenishing glutathione, a major antioxidant molecule. The interaction between glutamine and amino acid transporters—such as solute carrier family 1 members—modulates tumor cell metabolism, growth, and chemosensitivity. Importantly, extracellular glutamine levels in the TME correlate with tumor invasiveness, underscoring its role in promoting metastatic potential. ⁹²

Interaction of Adipose Derived Stem Cells (ASCs) With Breast Cancer Cells

ASCs, as a kind of pluripotent stem cells in adipose tissue, have attracted much attention in the research field of breast cancer in recent years. They are inextricably linked with breast cancer cells and profoundly affect the occurrence, development, invasion, metastasis and treatment response of breast cancer. ASC has strong self-renewal and multi-directional differentiation potential, and can differentiate into various cell types such as adipocytes, osteoblasts, chondrocytes, etc. under specific microenvironment stimuli. ⁹³ In the breast cancer TME, ASCs are recruited and activated, engaging in a complex bidirectional interaction with cancer cells. On one hand, ASCs secrete multiple growth factors—such as HGF—which enhance breast cancer cell migration via the HGF/c-Met signaling pathway. Concurrently, these cells establish an inflammatory microenvironment that promotes tumor angiogenesis and creates a permissive niche for cancer cell growth and proliferation, potentially facilitating breast cancer recurrence. ⁹⁴ ASCs secrete VEGF, which promotes tumor angiogenesis by activating the VEGF/VEGF-R signaling pathway. This process provides tumor cells with abundant oxygen and nutrients, thereby supporting their rapid proliferation. ⁹⁵ Tumor cells utilize TGF-β, secreted by ASCs, to drive their progression through the modulation of processes such as cell invasion, immune evasion, and microenvironmental remodeling. Specifically, TGF-β induces immunosuppressive microenvironments and facilitates tumor cell evasion of immune surveillance, thereby creating a permissive niche for tumor growth and metastasis ⁹⁶ ; Within the TME, ASCs may undergo transdifferentiation into CAFs, secreting ECM components such as collagen and fibronectin. These molecules provide a structural scaffold for tumor cell adhesion, remodeling the microenvironment to promote tumor cell survival. This process facilitates chemoresistance and cancer recurrence by creating a physical and biochemical niche that protects tumor cells from therapeutic interventions. ⁹⁷

Conversely, breast cancer cells reciprocally modulate the biological properties of ASCs. Soluble factors secreted by tumor cells, in conjunction with obesity-related stimuli, drive the differentiation of ASCs into CAFs. Notably, ASCs from obese individuals (obASCs) exhibit a higher propensity for this transdifferentiation compared with those from lean individuals (lnASCs). Transformed CAFs secrete a diverse array of bioactive molecules that promote tumor progression, underscoring the bidirectional crosstalk between cancer cells and the stromal microenvironment. ⁹⁸ These differentiated cells further enhance the pro-tumor properties of the TME by secreting an array of pro-tumor factors, including MMPs. These enzymes degrade the ECM, thereby facilitating tumor cell metastasis. Additionally, senescence-associated CAFs (senCAFs) inhibit NK cell-mediated cytotoxicity against tumor cells by secreting ECM components, which hinder NK cell infiltration into tumor tissue. This process promotes breast cancer progression and highlights a positive feedback loop between CAFs and breast cancer cells, whereby they collaboratively shape an immunosuppressive microenvironment to drive tumor advancement. ⁹⁹

Notably, ASCs can also exert tumor-suppressive effects during breast cancer progression. In vitro studies have demonstrated that ASCs or their secreted factors inhibit breast cancer cell proliferation, with SKBR3 cells showing reduced viability following exposure to ASC-conditioned media. Mechanistically, ASCs induce EMT in SKBR3 cells, concomitantly enhancing tumor sphere formation, cell fusion, and migratory capacity—paradoxically while significantly suppressing proliferation. This inhibitory phenotype is mediated by the SDF-1α/ CXCR4 signaling axis, highlighting the context-dependent dual roles of ASCs in regulating breast cancer cell behavior. ¹⁰⁰ In another set of experiments, adipose-derived mesenchymal stem cells (MSCs) co-cultured with MCF7 and MDA-MB-231 breast cancer cells secreted exosomes harboring specific miRNAs. These exosomes are transferred into cancer cells via intercellular communication, subsequently regulating key signaling pathways to inhibit tumor cell proliferation, migration, and invasion. Concurrently, they induce cell cycle arrest, promote a dormant state in cancer cells, and enhance resistance to chemotherapy—thereby impeding breast cancer progression. ¹⁰¹ The multifaceted roles and intricate mechanisms of ASCs within the breast cancer TME remain poorly characterized. Substantial research is required to further dissect their functional contributions, with a particular need to unravel the complex crosstalk between ASCs, cancer cells, and other stromal components. This ongoing investigation holds promise for uncovering novel therapeutic targets to disrupt tumor-stromal interactions and improve breast cancer management.

Conclusion

The TME, a complex niche comprising diverse cellular components and ECM, is central to tumor cell growth, proliferation, and metastasis, exerting a profound influence on breast cancer progression. Adipocytokines and other bioactive factors secreted by adipose tissue are integral to this process, with leptin, adiponectin, and resistin emerging as key mediators. Leptin activates JAK-STAT, PI3K-Akt, and MAPK signaling pathways, promoting breast cancer cell proliferation, migration, and invasion while suppressing anti-tumor immunity; adiponectin exerts potent oncostatic effects by activating the AMPK pathway and inhibiting mTOR signaling; resistin triggers NF-κB-mediated pro-tumorigenic programs, driving cancer cell growth, metastasis, and immune evasion. Beyond these, adipose tissue influences breast cancer development through miRNA secretion, metabolic pathway regulation, and bidirectional crosstalk between ASCs and cancer cells.

It is evident that there are numerous pivotal issues that remain unresolved. For instance, in the context of the interrelationship between adipocytokines and the TME, it remains ambiguous whether adipocytokines undergo a primary alteration, which subsequently influences the signaling pathway and culminates in modifications to the TME, thereby promoting the development of breast cancer. Alternatively, it is conceivable that the alterations within the TME may serve as the catalyst for a sequence of subsequent phenomena. Consequently, elucidating the initiating factors for the successive changes in these two domains will be a pivotal direction for future research endeavors. In the meantime, further research is required to determine whether other molecules, located upstream of adipocytokines or adipocytes, exert an influence on the downstream cascade reaction. A further key question that needs to be thoroughly investigated is whether the TME, as the background of cellular existence, may crosstalk between various signaling pathways and adipocytokines and inflammatory factors.

Current evidence underscores the intertwined roles of adipocytokines, inflammatory factors, and the TME in forming a highly complex regulatory network that drives breast cancer progression. Future therapeutic strategies may focus on: (1) developing targeted agents against key adipocytokines and their signaling axes; (2) modulating immune cell functions within the TME to enhance anti-tumor immune surveillance; (3) intervening in adipose–cancer cell metabolic crosstalk to disrupt cancer-supportive bioenergetic pathways. In-depth investigation of these unresolved questions and translation of findings into clinical applications hold promise for improving breast cancer prognosis and providing innovative solutions for this disease.