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The impact of obesity on the tumor microenvironment. White adipose tissue from an obese host is composed of hypertrophied adipocytes, some of which become necrotic and induce formation of crown-like structures. Adipose tissue inflammation is furthered by M1-like and metabolically activated macrophages. Tumors developing adjacent to obese adipose tissue receive numerous inflammatory and metabolic signals from adipose and are marked by immunosuppressed tumor microenvironment with ineffective tumor-infiltrating lymphocytes and immunosuppressive M2-like macrophage polarization. Adipose tissue further contributes to the tumor microenvironment via recruitment and transdifferentiation of cancer-associated fibroblasts from mesenchymal stem cells, and adipocyte-derived fibroblasts from adipocytes
Source publication
Obesity, exceptionally prevalent in the USA, promotes the incidence and progression of numerous cancer types including breast cancer. Complex, interacting metabolic and immune dysregulation marks the development of both breast cancer and obesity. Obesity promotes chronic low-grade inflammation, particularly in white adipose tissue, which drives imm...
Citations
... [3] Furthermore, obesity is associated with shorter distant recurrence-free survival (RFS) and overall survival (OS). [4,5] However, the mechanisms by which obesity exacerbates the prognosis of breast cancer remain unclear. ...
Background: Obese individuals diagnosed with breast cancer often experience a less favorable prognosis; however, the underlying mechanisms linking obesity to breast cancer outcomes remain elusive. This study aimed to identify and validate novel prognostic markers associated with breast cancer in patients with obesity. Methods: We conducted a reanalysis of gene expression profiles from normal-weight, overweight, and obese breast cancer patients to identify candidate genes. Subsequently, we validated the protein levels of these candidates using immunohistochemistry. Finally, we investigated the association between candidate genes and breast cancer prognosis at Tongji Hospital, utilizing data from an 8-year follow-up through the Kaplan-Meier method and univariate and multivariate Cox regression models. Results: The fold change of the circadian clock gene period 2 (PER2), which exhibited a declining trend with increasing body mass index, was 0.76 in obese patients compared with normal-weight patients. The expression rates of PER2 protein were 44.7%, 51.5%, and 61.3% in normal-weight, overweight, and obese patients, respectively. The 8-year recurrence-free survival rates were 75.9%, 69.6%, and 64.1%, whereas the 8-year overall survival rates were 86.8%, 83.0%, and 76.1% in normal-weight, overweight, and obese patients, respectively (P < 0.05). Furthermore, the 8-year recurrence-free survival rates were 66.2% and 76.4%, and the 8-year overall survival rates were 79.9% and 86.3% in the low and high PER2 expression groups, respectively (P < 0.05). The un-adjusted hazard ratio for PER2 was 1.550 (95% confidence interval, 1.029-2.335), and the adjusted hazard ratio was 3.003 (95% confidence interval, 1.838-4.907). Conclusions: Our findings indicate that low PER2 expression serves as an independent risk factor for breast cancer prognosis and may contribute to the unfavorable outcomes observed in obese patients.
... IL-6, IL-8, IL-1β). 14,15 Mouse models of PDAC and obesity have also demonstrated that weight-gain creates an inflammatory environment that aids cancer progression . [15][16][17] However, in vivo models are limited in their ability to isolate individual biophysical and biochemical elements within the microenvironment of either PDAC or obesity that contribute to disease progression, which limits the ability to identify potential targets or specific intervention strategies. ...
... 14,15 Mouse models of PDAC and obesity have also demonstrated that weight-gain creates an inflammatory environment that aids cancer progression . [15][16][17] However, in vivo models are limited in their ability to isolate individual biophysical and biochemical elements within the microenvironment of either PDAC or obesity that contribute to disease progression, which limits the ability to identify potential targets or specific intervention strategies. ...
Obesity is a leading risk factor of pancreatic ductal adenocarcinoma (PDAC) that contributes to poor disease prognosis and outcomes. Retrospective studies have identified this link, but interactions surrounding obesity and PDAC are still unclear. Research has shifted to contributions of fibrosis (desmoplasia) on malignancy, which involves increased deposition of collagens and other extracellular matrix (ECM) molecules and increased ECM crosslinking, all of which contribute to increased tissue stiffening. However, fibrotic stiffening is underrepresented as a model feature in current PDAC models. Fibrosis is shared between PDAC and obesity, and can be leveraged for in vitro model design, as current animal obesity models of PDAC are limited in their ability to isolate individual components of fibrosis to study cell behavior. In the current study, methacrylated type I collagen (PhotoCol®) was photo-crosslinked to pathological stiffness levels to recapitulate fibrotic ECM stiffening. PANC-1 cells were encapsulated within PhotoCol®, and the tumor-tissue constructs were prepared to represent normal (healthy) (∼600 Pa) and pathological (∼2000 Pa) tissues. Separately, human mesenchymal stem cells were differentiated into adipocytes representing lean (2D differentiation) and obese fat tissue (3D collagen matrix differentiation), and conditioned media was applied to PANC-1 tumor-tissue constructs. Conditioned media from obese adipocytes showed increased vimentin expression, a hallmark of invasiveness and progression, that was not seen after exposure to media from lean adipocytes or control media. Characterization of the obese adipocyte secretome suggested that some PANC-1 differences may arise from increased interleukin-8 and -10 compared to lean adipocytes. Additionally, high matrix stiffness associated induced an amoeboid morphology in PANC-1 cells that was not present at low stiffness. Amoeboid morphology is an accessory to epithelial-to-mesenchymal transition and is used to navigate complex ECM environments. This plasticity has greater implications for treatment efficacy of metastatic cancers. Overall, this work 1) highlights the importance of investigating PDAC-obesity interactions to study the effects on disease progression and persistence, 2) establishes PhotoCol® as a matrix material that can be leveraged to study amoeboid morphology and invasion in PDAC, and 3) emphasizes the importance of integrating both biophysical and biochemical interactions associated within both pathologies for in vitro PDAC models.
... Obesity is linked to changes in overall body physiology and hormonal balance that contribute to various health conditions like diabetes and cardiovascular diseases (10). Moreover, obesity is correlated with an elevated likelihood of developing several types of cancer and with reduced survival rates for individuals diagnosed with those cancers (11). The National Institute of Health (NIH) categorizes body mass index (BMI) as follows: underweight < 18.5 kg/m 2 , normal weight 18.5 to < 25 kg/m 2 , overweight 25.0 to < 30 kg/m 2 , and obesity ≥ 30.0 kg/m 2 (12). ...
Background
Obese breast cancer patients have worse prognosis than normal weight patients, but the level at which obesity is prognostically unfavorable is unclear. This study aimed to investigate different effects of Body Mass Index (BMI) on prognosis disease-free survival and overall survivor of breast cancer patients.
Method
This retrospective cohort study analyzed the medical records of breast cancer patients who sought treatment at Namazi hospital in Shiraz, Iran between 2014 and 2019. Three groups of patients were divided according to BMI. Menopausal status, BMI status, clinicopathological characteristics, treatment, and overall survival (OS), and disease free survival (DFS) were comprehensively evaluated.
Results
Of the 7134 breast cancer patients, the majority (42.6%) were in 25–30 kg/m². Menopausal status significantly were associated with obesity (P <0 .001). The majority of patients were categorized as grade 2 and stage 2 according to the BMI categories (P = 0.12, P = 0.08, respectively). BMI categories regardless of menopausal status displayed increased 1, 3, and 5-year DFS and 5- year OS in stage 1 and increased 1, 3, and 5-year OS and 1 and 3-year DFS in stage 2. In stage 3, the risks of relapse and death were significantly decreased in all three groups of BMI patients with post-menopausal period.
Conclusion
Obesity leads to worse DFS and OS in patients with BC and the effects of obesity on the breast cancer prognosis seem to be clinically related to menopausal status. Once validated, these results should be considered in the development of prevention programs.
... Obesity has been widely accepted as an important risk factor for breast cancer [15][16][17]. As early as 2018, Nattenmuller et al. found through histopathological analysis of 657 breast cancer patients that obesity was associated with a lower risk of invasive breast tumors [18]. ...
Objective
Breast cancer was the most common type of cancer among women worldwide, significantly impacting their quality of life and survival rates. And obesity has been widely accepted as an important risk factor for breast cancer. However, the specific mechanisms by which obesity affects breast cancer were still unclear. Therefore, studying the impact mechanisms of obesity as a risk factor for breast cancer was of utmost importance.
Methods
This study was based on TCGA breast cancer RNA transcriptomic data and the GeneCard obesity gene set. Through single and multiple factor Cox analysis and LASSO coefficient screening, seven hub genes were identified. The independent mechanisms of these seven hub genes were evaluated from various aspects, including survival data, genetic mutation data, single-cell sequencing data, and immune cell data. Additionally, the risk prognosis model and the neural network diagnostic model were established to further investigate these seven hub genes. In order to achieve precision treatment for breast cancer (BRCA), based on the RNA transcriptomic data of the seven genes, 1226 BRCA patients were divided into two subtypes: BRCA subtype 1 and BRCA subtype 2. By studying and comparing the immune microenvironment, investigating the mechanisms of differential gene expression, and exploring the mechanisms of subnetworks, we aim to explore the clinical differences in the presentation of BRCA subtypes and achieve precision treatment for BRCA. Finally, qRT-PCR experiments were conducted to validate the conclusions of the bioinformatics analysis.
Results
The 7 hub genes showed good diagnostic independence and can serve as excellent biomarkers for molecular diagnosis. However, they do not perform well as independent prognostic molecular markers for BRCA patients. When predicting the survival of BRCA patients, their AUC values at 1 year, 3 years, and 5 years are mostly below 0.5. Nevertheless, through the establishment of the risk prognosis model considering the combined effect of the seven hub genes, it was found that the survival prediction of BRCA patients can be significantly improved. The risk prognosis model, compared to the independent use of the seven hub genes as prognostic markers, achieved higher timeROC AUC values at 1 year, 3 years, and 5 years, with values of 0.651, 0.669, and 0.641 respectively. Additionally, the neural network diagnostic model constructed from the 7 genes performs well in diagnosing BRCA, with an AUC value of 0.94, accurately identifying BRCA patients. The two subtypes identified by the seven hub genes exhibited significant differences in survival period, with subtype 1 having a poor prognosis. The differential mechanisms between the two subtypes mainly originate from regulatory differences in the immune microenvironment. Finally, the results of this study’s bioinformatics analysis were validated through qRT-PCR experiments.
Conclusion
7 hub genes serve as excellent independent biomarkers for molecular diagnosis, and the neural network diagnostic model can accurately distinguish BRCA patients. In addition, based on the expression levels of these seven genes in BRCA patients, two subtypes can be reliably identified: BRCA subtype 1 and BRCA subtype 2, and these two subtypes showed significant differences in BRCA patient survival prognosis, proportion of immune cells, and expression levels of immune cells. Among them, patients with subtype 1 of BRCA had a poor prognosis.
... We previously reported that the presence of peritumoural adipose tissue in esophageal adenocarcinoma influences the migration and adhesion of cancer cells by exerting a paracrine effect 14,21 . Moreover, obesity is a strong predictor of breast cancer and is associated with more advanced disease, including larger size, highergrade, lymph node positivity, development of visceral metastases, lower distant disease-free interval and overall survival [33][34][35] . Cytokines and adipokines are the best characterized adipose tissue-released factors and increasing consensus points to a preferential response of tumours to the specific adjacent adipose tissue. ...
Obesity is associated with increased risk and worse prognosis of many tumours including those of the breast and of the esophagus. Adipokines released from the peritumoural adipose tissue promote the metastatic potential of cancer cells, suggesting the existence of a crosstalk between the adipose tissue and the surrounding tumour. Mitochondrial Ca²⁺ signaling contributes to the progression of carcinoma of different origins. However, whether adipocyte-derived factors modulate mitochondrial Ca²⁺ signaling in tumours is unknown. Here, we show that conditioned media derived from adipose tissue cultures (ADCM) enriched in precursor cells impinge on mitochondrial Ca²⁺ homeostasis of target cells. Moreover, in modulating mitochondrial Ca²⁺ responses, a univocal crosstalk exists between visceral adipose tissue-derived preadipocytes and esophageal cancer cells, and between subcutaneous adipose tissue-derived preadipocytes and triple-negative breast cancer cells. An unbiased metabolomic analysis of ADCM identified creatine and creatinine for their ability to modulate mitochondrial Ca²⁺ uptake, migration and proliferation of esophageal and breast tumour cells, respectively.
... The underlying biological and metabolic mechanisms linking obesity to BC are multiple and complex. Obesity has been strongly associated with several metabolic alterations, including deregulation of sex hormones, overexpression of pro-inflammatory cytokines, insulin resistance, hyperactivation of insulin-like growth factor (IGF) pathways, hypercholesterolemia, as well as excessive oxidative stress [5,[12][13][14]. Several of these biomarkers (such as serum sex hormone-binding globulin (SHBG), IGF-1, testosterone, C-reactive protein (CRP)) have also been associated with BC risk [15][16][17]. ...
... In agreement with our study, a study conducted in EPIC reported an increased risk for BC in relation to both body shape PC1 (general adiposity) and body shape PC2 (tall; low WHR) [10]. These results are also congruent with previous studies investigating the association between obesity and risk of BC, but using single-trait anthropometric indicators such as BMI [1,6,13]. ...
Body shape phenotypes combining multiple anthropometric traits have been linked to postmenopausal breast cancer (BC). However, underlying biological pathways remain poorly understood. This study investigated to what extent the associations of body shapes with postmenopausal BC risk is mediated by biochemical markers. The study included 176,686 postmenopausal women from UK Biobank. Four body shape phenotypes were derived from principal component (PC) analysis of height, weight, body mass index, waist and hip circumferences, and waist-to-hip ratio (WHR). The four-way decomposition of the total effect was used to estimate mediation and interaction effects simultaneously as well as the mediated proportions. After 10.9 years median follow-up, 6,396 incident postmenopausal BC were diagnosed. There was strong evidence of positive associations between PC1 (general obesity) and PC2 (tall, low WHR), and BC risk. The association of PC1 with BC risk was positively mediated by testosterone and negatively by insulin-like growth factor-1 (IGF-1), with the overall proportion mediated (sum of the mediated interaction and pure indirect effect (PIE)) accounting for 11.4% (95% confidence intervals: 5.1 to 17.8%) and -12.2% (-20.5% to -4.0%) of the total effect, respectively. Small proportions of the association between PC2 and BC were mediated by IGF-1 (PIE: 2.8% (0.6 to 4.9%)), and sex hormone-binding globulin (SHBG) (PIE: -6.1% (-10.9% to -1.3%)). Our findings are consistent with differential pathways linking different body shapes with BC risk, with a suggestive mediation through testosterone and IGF-1 in the relationship of a generally obese body shape and BC risk, while IGF-1 and SHBG may mediate a tall/lean body shape-BC risk association.
... It has the worst clinical outcomes with greater recurrence and lower overall survival rates. And there are no targeted therapies available yet [4,5]. According to the American Cancer Society, the overall 5-year relative survival rate for American patients with TNBC is 77%, compared with 90% for non-TNBC breast cancer. ...
Breast cancer, particularly triple-negative breast cancer (TNBC), poses a global health challenge. Emerging evidence has established a positive association between elevated levels of stearoyl-CoA desaturase 1 (SCD1) and its product oleate (OA) with cancer development and metas-tasis. SCD1/OA leads to alterations in migration speed, direction, and cell morphology in TNBC cells, yet the underlying molecular mechanisms remain elusive. To address this gap, we aim to investigate the impact of OA on remodeling the actin structure in TNBC cell lines, and the underlying signaling. Using TNBC cell lines and bioinformatics tools, we show that OA stimulation induces rapid cell membrane ruffling and enhances filopodia formation. OA treatment triggers the subcellular translocation of Arp2/3 complex and Cdc42. Inhibiting Cdc42, not the Arp2/3 complex, effectively abolishes OA-induced filopodia formation and cell migration. Additionally, our findings suggest that phospholipase D is involved in Cdc42-dependent filopodia formation and cell migration. Lastly, the elevated expression of Cdc42 in breast tumor tissues is associated with a lower survival rate in TNBC patients. Our study outlines a new signaling pathway in the OA-induced migration of TNBC cells, via the promotion of Cdc42-dependent filopodia formation, providing a novel insight for therapeutic strategies in TNBC treatment.
... The country witnessed a steady increase in breast cancer incidence rates, attributed partially to factors like the obesity epidemic and declining parity among women [35]. However, advancements in early detection and treatment have contributed to better control of breast cancer incidences and deaths [36]. ...
Breast cancer is considered a significant health concern worldwide, with genetic predisposition playing a critical role in its etiology. Single nucleotide polymorphisms (SNPs), particularly those within the 3' untranslated regions (3'UTRs) of target genes, are emerging as key factors in breast cancer susceptibility. Specifically, miRNAs have been recognized as possible novel approach for biomarkers discovery for both prognosis and diagnosis due to their direct association with cancer progression. Regional disparities in breast cancer incidence underscore the need for precise interventions, considering socio-cultural and economic factors. This review explores into the differential effects of SNP-miRNA interactions on breast cancer risk, emphasizing both risk-enhancing and protective associations across diverse populations. Furthermore, it explores the clinical implications of these findings, highlighting the potential of personalized approaches in breast cancer management. Additionally, it reviews the evolving therapeutic prospect of microRNAs (miRNAs), extending beyond cancer therapeutics to encompass various diseases, indicative of their versatility as therapeutic agents.
... Breast cancer occurrence, as well as the rate of metastasis, are strongly correlated with obesity, suggesting that fat tissue may have a role to play in the pathogenesis of breast cancers [6,7]. Both luminal type A breast cancer, which is more common in occurrence, as well as the basal subtypes correlate strongly with obesity [8]. ...
Simple Summary
Obesity is associated with increased occurrence and metastasis of breast cancer. Breast cancers are also very hypoxic and rich in adipose (fat) tissue. We found that adipocyte-derived stromal cells (ASCs) can transform normal breast epithelial cells to become invasive, potentiating them toward a cancerous state. We also found that unstable or fluctuating hypoxia, which is common in the tumor environment, can cause ASCs to become senescent, with an additive effect on breast epithelial potentiation to an invasive state.
Abstract
Obesity is strongly associated with occurrence, metastasis, and resistance to therapy in breast cancers, which also exhibit high adipose content in the tumor microenvironment. Adipose tissue-derived mesenchymal stromal cells (ASCs) are recruited to breast cancer by many mechanisms, including hypoxia, and contribute to metastatic transition of the cancer. Breast cancers are characterized by regions of hypoxia, which can be temporally unstable owing to a mismatch between oxygen supply and consumption. Using a high-sensitivity nanopatterned stromal invasion assay, we found that ASCs could promote stromal invasion of not only breast cancer cell lines but also MCF10A1, a cell line derived from untransformed breast epithelium. RNA sequencing of MCF10A1 cells conditioned with medium from ASCs revealed upregulation of genes associated with increased cell migration, chemotaxis, and metastasis. Furthermore, we found that fluctuating or oscillating hypoxia could induce senescence in ASCs, which could result in an increased invasive potential in the treated MCF10A1 cells. These findings highlight the complex interplay within the breast cancer microenvironment, hypoxia, and the role of ASCs in transforming even non-cancerous breast epithelium toward an invasive phenotype, providing insights into early metastatic events.
... While physical activity reduces activity of pro-oncogenic inflammatory pathways, obesity promotes a hypoxic and inflammatory cellular environment through the activity of leptin, vascular endothelial growth factors, and the infiltration of pro-inflammatory immune cells [16][17][18][19][20][21]. Further, in post-menopausal settings, estrogen biosynthesis is carried out predominately by aromatase in adipose tissue, while increased production of numerous pro-inflammatory adipokines in obese adipose tissue stimulates increased activity of aromatase, thereby increasing circulating estrogen [22,23]. ...
Breast cancer survival has increased significantly over the last few decades due to more effective strategies for prevention and risk modification, advancements in imaging detection, screening, and multimodal treatment algorithms. However, many have observed disparities in benefits derived from such improvements across populations and demographic groups. This review summarizes published works that contextualize modern disparities in breast cancer prevention, diagnosis, and treatment and presents potential strategies for reducing disparities. We conducted searches for studies that directly investigated and/or reported disparities in breast cancer prevention, detection, or treatment. Demographic factors, social determinants of health, and inequitable healthcare delivery may impede the ability of individuals and communities to employ risk-mitigating behaviors and prevention strategies. The disparate access to quality screening and timely diagnosis experienced by various groups poses significant hurdles to optimal care and survival. Finally, barriers to access and inequitable healthcare delivery patterns reinforce inequitable application of standards of care. Cumulatively, these disparities underlie notable differences in the incidence, severity, and survival of breast cancers. Efforts toward mitigation will require collaborative approaches and partnerships between communities, governments, and healthcare organizations, which must be considered equal stakeholders in the fight for equity in breast cancer care and outcomes.
