Age-related and postmenopausal breast cancer progression and treatment management: The significance of pro-inflammatory cytokines and CXC chemokines

Abstract

Older age is one of the leading risk indicators for advanced breast cancer. It is critical to extensively investigate how aging affects breast cancer, considering the increasing rate of population aging. Human body aging and death are caused by cellular senescence and alterations in the aging microenvironment in vivo. Breast cancer cells may invade more easily with age due to the stiff extracellular matrix of the breast. Furthermore, growing evidence suggests that the massive release of inflammatory immune mediators, such as cytokines (interleukins) or CXC chemokines (CXCs), and their receptors (CXCRs), including interleukin (IL)-6, IL-8/CXCL8, tumor necrosis factor (TNF), interferon (INF), transforming growth factor (TGF), CXCL1, CXCL9, CXCL10, CXCL11/CXCR3, and CXCL12/CXCR4, plays a critical role in the development of breast cancer in elderly patients. Researchers are particularly interested in obesity-induced inflammation because it has been shown to raise the risk of breast cancer in postmenopausal women with higher body mass index. Obesity-triggered inflammation causes increased infiltration of proinflammatory cytokines, adipokines, immune cells, and tumor cells in the enlarged adipose tissue of postmenopausal women with breast cancer, thereby modulating the tumor's immune-mediated microenvironment. Therefore, in this review, we focus on the functional significance studies of proinflammatory cytokines, CXCs, and CXCRs and describe their roles in influencing breast cancer progression in older women and their factors, such as obesity in postmenopausal women. In addition, the current status and prospects of cytokine- and CXC-based theranostic interventions for breast cancer therapy in elderly and postmenopausal women are discussed.

Keywords: Age; Breast cancer; CXC chemokines; Obesity; Postmenopausal women; Pro-inflammatory cytokines; Theranostic strategies.

Figure 1

Pro-inflammatory cytokines and the C-X-C motif chemokine (CXC) family members and their receptors. (A) A diagram of various cells that act as major sources of pro-inflammatory cytokines, including interleukins (ILs), natural killer (NK), tumor necrosis factor-alpha (TNF-α), mast cells, transforming growth factor-beta (TGF-β), granulocyte-macrophage colony-stimulating factor (GM-CSF), interferon gamma-induced protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), and monokine induced by gamma (MIG). (B) The classification of the CXC chemokine family.

Figure 2

The cytokine network in various molecular subtypes of breast cancer. (A) The cytokine network in luminal B HER2-positive subtype. (B) The cytokine network in triple-negative subtype.

Figure 3

Pro-inflammatory cytokines (interleukins/ILs) play a role in aged/postmenopausal breast cancer women or animal model/senescence cells, as depicted in the illustration. (A) Schematic diagram of legumain (Lgmn^−/− mice) deletion mediating the inhibition of tumor-associated macrophage (TAM) pro-tumor effects and promoting tumor senescence. TAM-derived legumain suppresses signal transducer and activator of transcription 1 (STAT1) signaling in an autocrine manner. Deletion of legumain led to the sustained activation of STAT1 signaling, stimulating inducible nitric oxide synthase (iNOS) expression and intracellular reactive oxygen species (ROS) accumulation, and thus contributing to the increased expression and secretion of IL-1β and promoting tumor senescence. The regulatory effect of legumain secretion on STAT1 inhibition via interaction with integrin αvβ3 in TAMs. (B) In aged patients, IL-6 is up-regulated, which recruits bone marrow cells and plays a role in the survival of tumor cells. These processes can be inhibited by tocilizumab/STING/interferon (IFN)/STAT1 pathways. IL-6 can stimulate the expression of lysine-specific demethylase 2A (KDM2A) in normal fibroblasts, transforming them into cancer-associated fibroblasts (CAFs). Up-regulation of KDM2A in these cells induces senescence in fibroblasts, which is dependent on p53, and enhances the release of IL-6. Inducing senescence in CAFs up-regulates programmed cell death-ligand 1 (PD-L1), which reduces the natural killer (NK) cells to target the tumor microenvironment (TME). The up-regulation of IL-6 induces chemoresistance and metastasis progression in triple-negative breast cancer (TNBC) through the Wnt-5 pathway. (C) In both in vitro and an animal model of breast cancer, the up-regulation of IL-8/C-X-C motif chemokine ligand 8 (CXCL8) induces senescent of breast cancer, inflammation, epithelial–mesenchymal transition (EMT), and stemness via the Janus kinase 2 (JAK2) and STAT3 pathways. The red color up arrow symbol (↑) represents up-regulation, while the down arrow symbol (↓) represents down-regulation.

Figure 4

Interleukin (IL)-10/11/tumor necrosis factor (TNF) and transforming growth factor (TGF) pro-inflammatory cytokines play a role in breast cancer in postmenopausal women and senescence cells, as shown in the illustration. (A) There is a correlation between higher expression of B-cell lymphoma 2 (Bcl-2) family proteins and IL-10, and they contribute to the aggressiveness of breast cancer via signal transducer and activator of transcription 3 (STAT3) pathway. The significant activation of IL-10 positive is correlated with mammographic density during breast cancer. Aged patients secrete a large amount of IL-11 and receptor IL-11Rα, which contribute to bone metastasis through the p-STAT3 pathway. (B) Higher levels of the inflammatory marker TNF-α are strongly associated with an increased risk of cancer-related mortality in elderly patients. TNF receptors, such as TNF-related apoptosis-inducing ligand (TRAIL) 1, 2, 3, and 4, play a crucial role in preventing cancer cell apoptosis and progression. However, TRAIL activation of death receptor 4/5 (DR4/5) promotes apoptosis in breast cancer cells but may also induce senescence. Endothelial cells (ECs) down-regulate the expression of TRAIL2, which reduces the apoptosis process in breast cancer. (C1) The breast cancer cell line MDA-MB-231 enhances surface proteoglycan syndecan 1 (SDC1) expression in young and senescent breast fibroblasts via TGF-β in a paracrine manner. On the other hand, exposure to ionizing radiation in early passage human breast stromal fibroblasts can cause premature senescence. This results in the formation of an autocrine TGF-β loop that leads to SDC1 overexpression via the Smad (small mothers against decapentaplegic) pathway. This suggests that ionizing radiation and invasive cancer cells have a synergistic effect leading to the overexpression of SDC1, which is a known poor prognostic factor in breast cancer development. (C2) TGF-β/connective tissue growth factor (CTGF) expression in stromal fibroblasts leads to reactive oxygen species (ROS) production, resulting in the stabilization of hypoxia-inducible factor 1 (HIF1)-transcription factor. HIF1-activation then promotes the induction of autophagy, mitophagy, and glycolysis. Autophagy drives the onset of senescence via the autophagy–senescence transition (AST), resulting in the up-regulation of cyclin-dependent kinase (CDK) inhibitors (p21 and p16 as well as β-galactosidase) (a lysosomal enzyme and marker of senescence). Oxidative stress, autophagy, and senescence may also contribute to CTGF-induced fibrosis and extracellular matrix (ECM) remodeling. The symbol of a red arrow pointing downwards (↓) is used to indicate down-regulation.

Figure 5

The stroma phenotype of catabolic tumor. (A) Reactive oxygen species (ROS) production by rapidly proliferating cancer cells causes oxidative stress in surrounding stromal cells, causing changes such as cancer-associated fibroblast (CAF) transformation, activation of hypoxia-inducible factor 1 (HIF1), nuclear factor-kappa B (NF-kB), transforming growth factor (TGF), or c-Jun N- terminal kinase (JNK)/activator protein 1 (AP1) signaling pathways, a switch to aerobic glycolysis and mitochondrial dysfunction, autophagy and senescence, and cytokine release: the catabolic tumor stroma phenotype. (B) Increased glycolysis and autophagy result in increased synthesis of energy-rich metabolites, such as lactate, which are produced by stromal cells and taken up by cancer cells, where they drive mitochondrial metabolism and adenosine triphosphate (ATP) production. Chemotherapy promotes the antioxidant response, immunological response, and stemness in cancer cells by inducing the catabolic tumor stroma phenotype. (C) Chemotherapy-induced DNA damage activates the HIF1, NF-kB, TGF, signal transducer and activator of transcription 3 (STAT3), and JNK/AP1 signaling pathways in stromal cells, promoting CAF differentiation, a switch to aerobic glycolysis and mitochondrial dysfunction, autophagy and senescence, the release of inflammatory cytokines, and the inhibition of interferon-mediated signaling. (D) When cancer cells encounter these catabolic fibroblasts, they respond to chemotherapy by activating antioxidant and immune response signals, as well as stemness. The red color up arrow symbol (↑) represents up-regulation, while the down arrow symbol (↓) represents down-regulation.

Figure 6

Pro-inflammatory C-X-C motif chemokines (CXCs) play a crucial role in the progression and development of breast cancer in aged patients, postmenopausal women, animal models, and senescent cells. (A1) The overexpression of CXCL1 leads to invasion and migration in breast cancer cells through the nuclear factor-kappa B (NF-kB)/SRY-box transcription factor 4 (SOX4) pathway. On the other hand, a high number of CXC chemokines are associated with the expression of osteopontin (OPN), which promotes tumor invasiveness and progression and reduces the overall survival (OS) rate. (A2) In the breast cancer mouse model, the primary breast cancer alters the lipid metabolism of lung fibroblasts by acetyl-CoA carboxylase alpha (ACACA) down-regulation. Lung fibroblasts convert to a senescent phenotype, which increases the recruitment of granulocyte myeloid-derived suppressor cells (G-MDSCs) by CXCL1 production, which induces an inflammatory lung microenvironment. (B1) Therapy-induced senescent epithelial cells can secrete senescence-associated secretory phenotype (SASP) factors that promote the invasion of breast cancer cells through the CXCL11/CXCR3/Ak strain transforming (AKT)/extracellular signal-regulated kinase (ERK) pathway. (B2) In older breast cancer patients, the secretion of TILRR (FREM1 isoform 2) is positively associated with the presence of immune cells like CD4⁺ and CD8⁺ T cells, CD86⁺ M1 macrophages, and the expression levels of CXCL10 and CXCL11. These factors are believed to be indicative of poor OS and recurrence-free survival (RFS). (C) The angiotensin II type I receptor (AGTR1) signaling regulates breast cancer migration and lymph node metastasis through the CXCL12/CXCR4 pathway. AGTR1 increases the level of CXCL12 in the lymph node, which attracts tumors that highly express CXCR4 cells. The mechanism behind AGTR1-induced migration and invasion of tumor cells involves up-regulating CXC12/CXCR4, Via focal adhesion kinase (FAK), and Ras homolog gene family member A (RhoA) molecules. (D) An aged breast cancer patient secretes a significant amount of CXCL13/CXCR5, which leads to lymph node metastasis, vascular invasion, and increased breast cancer cell survival.

Figure 7

Osteopontin (OPN)-activated cancer-associated fibroblast (CAF)-derived C-X-C motif chemokine ligand 12 (CXCL12) promotes epithelial-to-mesenchymal transition (EMT) in breast cancer cells. OPN plays a critical role in the transdifferentiation of fibroblasts into CAFs via cluster of differentiation 44 (CD44) and integrin-mediated Ak strain transforming (Akt) and extracellular signal-regulated kinase (ERK)-dependent Twist1 expression and CXCL12, which eventually regulate breast cancer progression.

Figure 8

Obese and postmenopausal breast cancer women exhibit the involvement of pro-inflammatory cytokines (interleukins/ILs), as shown in the illustration. (A) Obese and postmenopausal women secrete a large amount of IL-1/IL-RA, which is correlated with body mass index (BMI). This secretion occurs via the Wnt signaling pathway in mammary tissue, promoting breast cancer. IL-1 also plays a role in decreasing insulin concentration, leading to chemotherapy resistance, fatigue, and increased risk of breast cancer. IL-6 is found to be correlated with BMI and can induce inflammation through the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3)/Wnt pathways. It is also correlated with aromatase and resistin, which are known to increase the malignancy of ER⁺ breast cancer and metastasis. Furthermore, IL-6 can impair the receptors of natural killer (NK) cells. The secretion of IL-8/C-X-C motif chemokine ligand 8 (CXCL8) induces insulin degradation and chemotherapy resistance. IL-10 secretion inhibits the secretion of aromatase via suppressing tumor necrosis factor (TNF)-stimulated extracellular signal-regulated kinase (ERK) 1/2 activation. In addition, the excessive secretion of IL-12 can cause fatigue. The secretion of interferon-gamma (IFN-γ) can induce inflammation via nuclear factor-kappa B (NF-kB). TNF-α, on the other hand, promotes breast cancer progression through the Wnt pathway. Additionally, TNF-α plays a role in increasing fat diameter and induces insulin resistance through aromatase while also being involved in the synthesis of IL-6. The secretion of transforming growth factor-beta (TGF-β) also contributes to an increase in fat diameter, induces inflammation, and promotes tumor progression. (B) The mechanism of how breast cancer susceptibility gene 1 (BRCA1)-deficient adipose-derived stem cells promote breast cancer progression. BRCA1-deficient adipose-derived stem cells are unable to repair both spontaneous and stress-induced DNA damage. This accumulation of DNA damage leads to a more persistently active ataxia-telangiectasia mutated (ATM) complex, which activates p21 and induces cellular senescence. In the senescent state, BRCA1-deficient adipose-derived stem cells secrete an increased number of inflammatory cytokines, which promotes breast tumor proliferation and invasion. (C) Ovariectomized (OVX) mouse models, commonly used in menopausal and breast cancer research, exhibit altered immunological parameters. In particular, the cytokine IL-6 up-regulates sensitized breast cancer cells to low levels of testosterone; on the other hand, the OVX model reduces the anti-inflammatory cytokines IL-2 and IL-4. The red color up arrow symbol (↑) represents up-regulation, while the down arrow symbol (↓) represents down-regulation.