Obesity, Leptin and Breast Cancer: Epidemiological Evidence and Proposed Mechanisms

The prevalence of obesity has been steadily increasing over the past few decades in several developed and developing countries, with resultant hazardous health implications. Substantial epidemiological evidence has shown that excessive adiposity strongly influences risk, prognosis, and progression of various malignancies, including breast cancer. Indeed, it is now well recognized that obesity is a complex physiologic state associated with multiple molecular changes capable of modulating the behavior of breast tumor cells as well of the surrounding microenvironment. Particularly, insulin resistance, hyperactivation of insulin-like growth factor pathways, and increased levels of estrogen due to aromatization by the adipose tissue, inflammatory cytokines, and adipokines contribute to breast cancerogenesis. Among adipokines, leptin, whose circulating levels increase proportionally to total adipose tissue mass, has been identified as a key member of the molecular network in obesity. This review summarizes the current knowledge on the epidemiological link existing between obesity and breast cancer and outlines the molecular mechanisms underlying this connection. The multifaceted role of the obesity adipokine leptin in this respect is also discussed.

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Cellular and Molecular Players in the Interplay between Adipose Tissue and Breast Cancer

International Journal of Molecular Sciences ◽

10.3390/ijms22031359 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1359

Author(s):

Francesca Reggiani ◽

Paolo Falvo ◽

Francesco Bertolini

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Metabolic Disorders ◽

Current Knowledge ◽

Therapeutic Interventions ◽

Preclinical Research ◽

The World ◽

Adipose Cells

The incidence and severity of obesity are rising in most of the world. In addition to metabolic disorders, obesity is associated with an increase in the incidence and severity of a variety of types of cancer, including breast cancer (BC). The bidirectional interaction between BC and adipose cells has been deeply investigated, although the molecular and cellular players involved in these mechanisms are far from being fully elucidated. Here, we review the current knowledge on these interactions and describe how preclinical research might be used to clarify the effects of obesity over BC progression and morbidity, with particular attention paid to promising therapeutic interventions.

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A Tale of Three Systems: Toward a Neuroimmunoendocrine Model of Obesity

Annual Review of Cell and Developmental Biology ◽

10.1146/annurev-cellbio-120319-114106 ◽

2021 ◽

Vol 37 (1) ◽

pp. 549-573

Author(s):

Conan J.O. O'Brien ◽

Emma R. Haberman ◽

Ana I. Domingos

Keyword(s):

Adipose Tissue ◽

Energy Homeostasis ◽

Current Knowledge ◽

Neural Circuitry ◽

Leptin Resistance ◽

Direct Role ◽

Adipose Tissues ◽

Adipose Tissue Macrophages ◽

Prevalence Of Obesity ◽

Established Role

The prevalence of obesity is on the rise. What was once considered a simple disease of energy imbalance is now recognized as a complex condition perpetuated by neuro- and immunopathologies. In this review, we summarize the current knowledge of the neuroimmunoendocrine mechanisms underlying obesity. We examine the pleiotropic effects of leptin action in addition to its established role in the modulation of appetite, and we discuss the neural circuitry mediating leptin action and how this is altered with obesity, both centrally (leptin resistance) and in adipose tissues (sympathetic neuropathy). Finally, we dissect the numerous causal and consequential roles of adipose tissue macrophages in obesity and highlight recent key studies demonstrating their direct role in organismal energy homeostasis.

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Obesity and Breast Cancer: A Case of Inflamed Adipose Tissue

Cancers ◽

10.3390/cancers12061686 ◽

2020 ◽

Vol 12 (6) ◽

pp. 1686 ◽

Cited By ~ 3

Author(s):

Ryan Kolb ◽

Weizhou Zhang

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Molecular Mechanisms ◽

Breast Cancer Incidence ◽

Menopausal Status ◽

Epidemiological Data ◽

Adipose Tissue Inflammation ◽

Tissue Inflammation ◽

Cancer Subtypes ◽

Increased Risk

Obesity is associated with an increased risk of estrogen receptor-positive breast cancer in postmenopausal women and a worse prognosis for all major breast cancer subtypes regardless of menopausal status. While the link between obesity and the pathogenesis of breast cancer is clear, the molecular mechanism of this association is not completely understood due to the complexity of both obesity and breast cancer. The aim of this review is to highlight the association between obesity and breast cancer and discuss the literature, which indicates that this association is due to chronic adipose tissue inflammation. We will discuss the epidemiological data for the association between breast cancer incidence and progression as well as the potential molecular mechanisms for this association. We will focus on the role of inflammation within the adipose tissue during the pathogenesis of breast cancer. A better understanding of how obesity and adipose tissue inflammation affects the pathogenesis of breast cancer will lead to new strategies to reduce breast cancer risk and improve patient outcomes for obese patients.

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Adipocytes and microRNAs Crosstalk: A Key Tile in the Mosaic of Breast Cancer Microenvironment

Cancers ◽

10.3390/cancers11101451 ◽

2019 ◽

Vol 11 (10) ◽

pp. 1451 ◽

Cited By ~ 7

Author(s):

Erika Bandini ◽

Tania Rossi ◽

Giulia Gallerani ◽

Francesco Fabbri

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Immune Cells ◽

Tumor Suppressor Genes ◽

Breast Tissue ◽

Molecular Mechanisms ◽

Important Target ◽

New Concepts ◽

Clinical Strategies

Breast cancer (BC) is a disease characterized by a high grade of heterogeneity. Consequently, despite the great achievements obtained in the last decades, most of the current therapeutic regimens still fail. The identification of new molecular mechanisms that will increase the knowledge of all steps of tumor initiation and growth is mandatory in finding new clinical strategies. The BC microenvironment, consisting of endothelial cells, fibroblasts, immune cells and adipocytes, plays an essential role in regulating BC development, and recently it has gained great attention in the scientific community. In particular, adipose tissue is emerging as an important target to investigate among mammary gland components. The mechanisms underlying BC progression driven by adipocytes are predominantly unexplored, especially that involving the switch from normal adipocytes to the so-called cancer-associated adipocytes (CAAs). MicroRNAs (miRNAs), a class of gene expression modulators, have emerged as the regulators of key oncogenes and tumor suppressor genes that affect multiple pathways of the tumor microenvironment and adipose tissue. This review concerns a presentation of the role of adipocytes in breast tissue, and describes the most recent discoveries about the interplay between adipocytes and miRNAs, which collaborate in the arrangement of a pro-inflammatory and cancerous microenvironment, laying the foundations for new concepts in the prevention and treatment of BC.

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Inflammasomes in the Pathophysiology of Maternal Obesity: Potential Therapeutic Targets to Reduce Long-Term Adverse Health Outcomes in the Mother and Offspring

Current Vascular Pharmacology ◽

10.2174/1570161118666200603131536 ◽

2020 ◽

Vol 19 (2) ◽

pp. 165-175

Author(s):

Padma Murthi ◽

Gayathri Rajaraman

Keyword(s):

Health Outcomes ◽

Molecular Mechanisms ◽

Maternal Obesity ◽

Current Knowledge ◽

Protein Complexes ◽

Reproductive Age ◽

Adverse Health ◽

Adverse Health Outcomes ◽

Self Assembling ◽

Prevalence Of Obesity

: Over the past 20 years, the prevalence of obesity has risen dramatically worldwide, with an increase in occurrence among women in their reproductive age. Obesity during pregnancy is associated with significantly increased maternal and fetal morbidity and mortality. In addition to the short-term adverse health outcomes, both mother and the child are prone to develop cardiovascular, metabolic and neurological disorders. Although associations between obesity during pregnancy and adverse maternalfetal health outcomes are clear, the complex molecular mechanisms underlying maternal obesity remain largely unknown. This review describes multimeric self-assembling protein complexes, namely inflammasomes, as potential molecular targets in the pathophysiology of maternal obesity. Inflammasomes are implicated in both normal physiological and in pathophysiological processes that occur in response to an inflammatory milieu throughout gestation. This review highlights the current knowledge of inflammasome expression and its activity in pregnancies affected by maternal obesity. Key discussions in defining pharmacological inhibition of upstream as well as downstream targets of the inflammasome signaling cascade; and the inflammasome platform, as a potential therapeutic strategy in attenuating the pathophysiology underpinning inflammatory component in maternal obesity are presented herein.

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Mechanisms of Resistance to CDK4/6 Inhibitors in Breast Cancer and Potential Biomarkers of Response

Breast Care ◽

10.1159/000484167 ◽

2017 ◽

Vol 12 (5) ◽

pp. 304-308 ◽

Cited By ~ 21

Author(s):

Cristina Guarducci ◽

Martina Bonechi ◽

Giulia Boccalini ◽

Matteo Benelli ◽

Emanuela Risi ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Molecular Mechanisms ◽

Randomized Clinical Trials ◽

De Novo ◽

Current Knowledge ◽

Acquired Resistance ◽

Metastatic Breast ◽

Molecular Alterations ◽

Potential Biomarkers

Randomized clinical trials demonstrated that CDK4/6 inhibitors are highly effective in patients with hormone receptor-positive (HR+), HER2-negative (HER2-) metastatic breast cancer in combination with endocrine therapy. The use of CDK4/6 inhibitors in clinics is becoming common for patients with HR+/HER2- metastatic breast cancer and will certainly increase in the near future. However, patients might show de novo or acquired resistance to these drugs. Molecular alterations have been suggested as determinants for de novo resistance to CDK4/6 inhibitors, but have never been validated in a clinical setting. In addition, molecular mechanisms of acquired resistance to palbociclib have been analyzed only in preclinical studies. Here we review the current knowledge on the available preclinical data about the mechanisms of de novo and acquired resistance to CDK4/6 inhibitors in breast cancer, and clinical data about potential biomarkers of response.

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Local Biomarkers Involved in the Interplay between Obesity and Breast Cancer

Cancers ◽

10.3390/cancers13246286 ◽

2021 ◽

Vol 13 (24) ◽

pp. 6286

Author(s):

Jonas Busk Holm ◽

Ann H. Rosendahl ◽

Signe Borgquist

Keyword(s):

Breast Cancer ◽

Adipose Tissue ◽

Current Knowledge ◽

Local Environment ◽

Aromatase Activity ◽

Breast Cancer Patients ◽

Increased Risk ◽

Breast Adipose Tissue ◽

Breast Adipose ◽

Inflammatory State

Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed.

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Leptin and Beyond: Actors in Cancer

Biomolecules ◽

10.3390/biom11121836 ◽

2021 ◽

Vol 11 (12) ◽

pp. 1836

Author(s):

Ines Barone ◽

Cinzia Giordano

Keyword(s):

Immune Response ◽

Adipose Tissue ◽

Energy Homeostasis ◽

Peptide Hormone ◽

Tissue Mass ◽

Adipose Tissue Mass ◽

Control Food ◽

Total Adipose Tissue ◽

Control Food Intake ◽

Reproductive Processes

Leptin is a 16-kDa multifunctional, neuroendocrine peptide hormone secreted by adipocytes in proportion to total adipose tissue mass, known to control food intake, energy homeostasis, immune response, and reproductive processes [...]

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The Anticancer Properties of Silibinin: Its Molecular Mechanism and Therapeutic Effect in Breast Cancer

Anti-Cancer Agents in Medicinal Chemistry ◽

10.2174/1871520620666191220142741 ◽

2020 ◽

Vol 20 (15) ◽

pp. 1787-1796

Author(s):

Agata Binienda ◽

Sylwia Ziolkowska ◽

Elzbieta Pluciennik

Keyword(s):

Breast Cancer ◽

Therapeutic Strategy ◽

Molecular Mechanisms ◽

Epithelial To Mesenchymal Transition ◽

Current Knowledge ◽

Mesenchymal Transition ◽

Anticancer Properties ◽

Main Component ◽

Inhibit Cell Proliferation ◽

Inflammatory Effect

Background: Silibinin (SB), the main component of Silymarin (SM), is a natural substance obtained from the seeds of the milk thistle. SM contains up to 70% of SB as two isoforms: A and B. It has an antioxidant and anti-inflammatory effect on hepatocytes and is known to inhibit cell proliferation, induce apoptosis, and curb angiogenesis. SB has demonstrated activity against many cancers, such as skin, liver, lung, bladder, and breast carcinomas. Methods: his review presents current knowledge of the use of SM in breast cancer, this being one of the most common types of cancer in women. It describes selected molecular mechanisms of the action of SM; for example, although SB influences both Estrogen Receptors (ER), α and β, it has opposite effects on the two. Its action on ERα influences the PI3K/AKT/mTOR and RAS/ERK signaling pathways, while by up-regulating ERβ, it increases the numbers of apoptotic cells. In addition, ERα is involved in SB-induced autophagy, while ERβ is not. Interestingly, SB also inhibits metastasis by suppressing TGF-β2 expression, thus suppressing Epithelial to Mesenchymal Transition (EMT). It also influences migration and invasive potential via the Jak2/STAT3 pathway. Results: SB may be a promising enhancement of BC treatment: when combined with chemotherapeutic drugs such as carboplatin, cisplatin, and doxorubicin, the combination exerts a synergistic effect against cancer cells. This may be of value when treating aggressive types of mammary carcinoma. Conclusion: Summarizing, SB inhibits proliferation, induces apoptosis, and restrains metastasis via several mechanisms. It is possible to combine SB with different anticancer drugs, an approach that represents a promising therapeutic strategy for patients suffering from BC.

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Oxygenated Water Inhibits Adipogenesis and Attenuates Hepatic Steatosis in High-Fat Diet-Induced Obese Mice

International Journal of Molecular Sciences ◽

10.3390/ijms21155493 ◽

2020 ◽

Vol 21 (15) ◽

pp. 5493

Author(s):

Yuh-Jen Cheng ◽

Chao-Chi Liu ◽

Fang-Yeh Chu ◽

Ching-Ping Yang ◽

Chiao-Wan Hsiao ◽

...

Keyword(s):

Adipose Tissue ◽

Glucose Tolerance ◽

Hepatic Steatosis ◽

Molecular Mechanisms ◽

Metabolic Effects ◽

Metabolic Function ◽

Tissue Mass ◽

Lipid Contents ◽

Oxygenated Water

The expansion of adipose tissue mass is the primary characteristic of the process of becoming obesity, which causes chronic adipose inflammation and is closely associated with type 2 diabetes mellitus (T2DM). Adipocyte hypertrophy restricts oxygen availability, leading to microenvironmental hypoxia and adipose dysfunction. This study aimed at investigating the effects of oxygenated water (OW) on adipocyte differentiation (adipogenesis) and the metabolic function of mature adipocytes. The effects of OW on adipogenesis and the metabolic function of mature adipocytes were examined. Meanwhile, the in vivo metabolic effects of long-term OW consumption on diet-induced obesity (DIO) mice were investigated. OW inhibited adipogenesis and lipid accumulation through down-regulating critical adipogenic transcription factors and lipogenic enzymes. While body weight, blood and adipose parameters were not significantly improved by long-term OW consumption, transient circulatory triglyceride-lowering and glucose tolerance-improving effects were identified. Notably, hepatic lipid contents were significantly reduced, indicating that the DIO-induced hepatic steatosis was attenuated, despite no improvements in fibrosis and lipid contents in adipose tissue being observed in the OW-drinking DIO mice. The study provides evidence regarding OW’s effects on adipogenesis and mature adipocytes, and the corresponding molecular mechanisms. OW exhibits transient triglyceride-lowering and glucose tolerance-improving activity as well as hepatic steatosis-attenuating functions.

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