The weight of obesity in breast cancer progression and metastasis: Clinical and molecular perspectives

Seminars in Cancer Biology xxx (xxxx) xxx–xxx

Contents lists available at ScienceDirect

Seminars in Cancer Biology journal homepage: www.elsevier.com/locate/semcancer

The weight of obesity in breast cancer progression and metastasis: Clinical and molecular perspectives ⁎

Ines Baronea, , Cinzia Giordanoa,b, Daniela Bonofiglioa, Sebastiano Andòa,b,1, ⁎ Stefania Catalanoa, ,1 a b

Department of Pharmacy, Health and Nutritional Sciences, Via P Bucci, 87036, Rende, CS, Italy Centro Sanitario, University of Calabria, Via P Bucci, 87036, Rende, CS, Italy

A R T I C LE I N FO

A B S T R A C T

Keywords: Breast cancer Metastasis Obesity Adipokines Leptin

The escalating epidemic of overweight and obesity is currently recognized as one of the most significant health and economic concern worldwide. At the present time, over 1.9 billion adults and more than 600 million people can be, respectively, classified as overweight or obese, and numbers will continue to increase in the coming decades. This alarming scenario implies important clinical implications since excessive adiposity can progressively cause and/or exacerbate a wide spectrum of co-morbidities, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and even certain types of cancer, including breast cancer. Indeed, pathological remodelling of white adipose tissue and increased levels of fat-specific cytokines (mainly leptin), as a consequence of the obesity condition, have been associated with several hallmarks of breast cancer, such as sustained proliferative signaling, cellular energetics, inflammation, angiogenesis, activating invasion and metastasis. Different preclinical and clinical data have provided evidence indicating that obesity may worsen the incidence, the severity, and the mortality of breast cancer. In the present review, we will discuss the epidemiological connection between obesity and breast cancer progression and metastasis and we will highlight the candidate players involved in this dangerous relationship. Since the major cause of death from cancer is due to widespread metastases, understanding these complex mechanisms will provide insights for establishing new therapeutic interventions to prevent/blunt the effects of obesity and thwart breast tumor progression and metastatic growth.

1. Introduction According to the latest cancer data accessible from the GLOBOCAN 2018 database, breast cancer is one of the most frequently diagnosed cancers among women across the globe, with over 2 million new cases estimated in 2018. It also ranks as the leading cause of cancer-related mortality in women worldwide, accounting for 627 000 deaths. Despite improved adjuvant treatment has resulted in better prognosis, up to 30% of node-negative breast cancer patients and an even larger proportion of patients with node-positive disease will develop deadly metastases, usually years after the time of primary tumor detection and surgical resection [1,2]. The most common metastatic organs are bone, lung, brain and liver. Once distant recurrence has occurred, the disease remains mainly incurable and median survival of women with metastatic breast cancer (MBC) ranges from two to three years [1]. A better comprehension of the incidence/survival rate for MBC as well as of the

related risk factors leading to MBC may help to identify patients at higher risk of progression, thus reducing the occurrence of advanced disease and improving the prognosis by early intervention. On the other hand, understanding these mechanisms will have implications for future molecularly targeted therapy. In the present review, we will outline obesity as an underlying determinant of breast cancer progression and metastasis. First, the cellular and molecular basis of breast cancer metastasis will be discussed. Then, the link between obesity and breast cancer progression will be underlined. Finally, leptin will be highlighted as the main candidate player involved in this dangerous relationship. 2. Breast cancer metastasis process In 1889, the English surgeon Stephen Paget illustrated ‘the seed and soil’ hypothesis on metastasis with the sentence ‘When a plant goes to

⁎*

Corresponding authors at: Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende CS, 87036, Italy. E-mail addresses: [email protected] (I. Barone), [email protected] (S. Catalano). 1 Joint senior authors. https://doi.org/10.1016/j.semcancer.2019.09.001 Received 12 July 2019; Accepted 1 September 2019 1044-579X/ © 2019 Elsevier Ltd. All rights reserved.

Please cite this article as: Ines Barone, et al., Seminars in Cancer Biology, https://doi.org/10.1016/j.semcancer.2019.09.001

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2.3. Survival in the circulation

seed, its seeds are carried in all directions, but they can only live and grow if they fall on congenial soil’ [3]. Therefore, the outcome of a metastatic process relies on both the intrinsic properties of neoplastic cells and the responses of the host tissue. The invasion-metastasis process can be described as a complex cascade of six chronologically/ functionally well-defined and interrelated steps, represented by: i) local invasion, ii) intravasation, iii) survival in the circulation, iv) arrest at distant organ site and extravasation, v) micrometastasis formation, and vi) metastatic outgrowth [4,5]. Each of these steps can be rate-limiting, since failure or an insufficiency at any levels can halt the whole process [4].

Breast cancer cell survival in the vasculature is most likely an essential step limiting the success rate of metastasis formation. Several challenges, such as mechanical destruction due to the hemodynamic shear forces in the bloodstream and surveillance by immune cells, especially natural killer cells (NK), contribute to make blood a hostile environment for circulating tumor cells (CTCs). Indeed, it has been estimated that less than 0.01% of CTCs have a chance to produce secondary lesions [16]. Different mechanisms governing CTC survival in the circulation have been proposed, although this issue is still under debate. CTCs exhibited genetic alterations (e.g. apoptosis-related genes) and abnormal gene expression (e.g. survivin, EGF and immunosuppressive molecules) as compared to the primary tumor cells [17]. It has been proposed that a subset of CTCs, consisting of CSCs, present a stemness profile [18]. Tumor cells may also protect themselves by expressing molecules (e.g. thrombin, cathepsin B, cancer procoagulant, receptor for coagulation factors and MMP-2/-14) to stimulate tumor cell-induced platelet aggregation. This platelet ‘coat’ may facilitate extravasation and consequent arrest at distant organ sites [19]. Moreover, immune cells, especially myeloid-derived suppressor cells (MDSCs), could aid the CTC escape from host immunity [20]. Neutrophils escort CTCs to support cell cycle progression and expand their metastatic potential [21]. Intriguingly, the formation of circulating tumor microemboli (CTMs), composed of at least 2 CTCs with large microemboli containing > 50 CTCs, has been associated with a high potential of metastasis by preserving cell clonal proliferation as well as protecting the innermost cells from blood stresses, anoikis, and immune surveillance [17].

2.1. Local invasion Local invasion begins with the migration of cancer cells from a wellconfined primary tumor into the surrounding stroma and subsequently into the adjacent normal tissue. This event characterizes the transition from an intraepithelial carcinoma Tis to a T1 tumor stage. At this step, primary epithelial tumor cells undergo a series of morphological and biochemical changes to achieve a mesenchymal phenotype associated with high motility and resistance to anoikis in a process known as epithelial-mesenchymal transition (EMT) [6]. EMT starts by losing the cell junction proteins involved in the epithelial organization, such as Ecadherin, claudins, occludins, and catenins, followed by the expression of mesenchymal markers, including N-cadherin and vimentin. This switch in cell traits and properties is mediated by a large number of oncogenic molecules [e.g. Transforming Growth Factor-β (TGF-β), Epidermal Growth Factor (EGF) and Insulin-like Growth Factor (IGF)] and a set of key transcription factors, named as EMT-activating transcription factors (e.g. Snail, Slug, Twist and ZEB-1/-2) [7]. The molecular events orchestrating EMT and conferring anoikis resistance can activate the migratory machinery in tumor cells through the members of the Rho GTPase family, leading to lamellipodia, filopodia and invadopodia formation [8]. After detachment from the primary tumor, EMT, migration, and invasion through the basement membrane, tumor cells can directly invade and degrade the extracellular matrix (ECM) by releasing a wide variety of proteases, as matrix metalloproteinase (MMP)-1, -2, and -9 and activating the proteolytic urokinase-type plasminogen activator system (uPA/uPAR) [9]. Importantly, during progression, malignant breast cells gain the capacity to recruit and reprogram the biology and the function of host stromal cells, including adipocytes, fibroblasts, endothelial cells, various bone marrow-derived cells and infiltrating cells of the immune system. This may enhance aggressive tumor behaviors through various types of heterotypic signalings and contribute to the promotion of an immune-suppressive environment [10]. The stroma-rich environment is also a source of developmental and self-renewal signals, including NOTCH, Hedgehog and WNT pathways, which support the fitness and survival of breast cancer stem cells (BCSCs), a small fraction of cancer cells with increased EMT, migration and invasion potential [11].

2.4. Arrest at distant organ sites and extravasation The next step of the invasion-metastasis cascade is extravasation, during which cancer cells adhere to vascular endothelium in the target organ and leave the circulation. This event is associated with the expression of specific cell adhesion molecules and secretion of factors inducing vascular hyper-permeability (e.g. angiopoietin like-4) [22,23]. The extravasation of breast cancer cells is also promoted by the expression of EGF, epiregulin, the prostaglandin-synthesizing enzyme cyclooxygenase 2 (COX2), and MMP-1 and MMP-2 [24,25]. Breast cancer frequently metastasizes to sites, such as lung, bone, liver and brain, that have no direct vascular connections with the mammary gland tissue. This tropism has been associated with distinct genetic programs for each metastatic site [25–27]. In addition, the release of organ-specific chemokines and the expression of appropriate chemokine receptors on the surface of the tumor may help tumor cells to target their specific soil. In this context, the involvement of CXCL12/ CXCR4 axis has been widely recognized. CXCR4 expression in breast cancer cells induces metastasis by homing of tumor cells to organs with high CXCL12 levels, such as bone, lung, and brain [28]. Other proteins, including VCAM-1, NF-κB, JAGGED1, Osteopontin have been involved in breast cancer colonization of the bone [26,29,30], whereas the extracellular matrix components tenascin C (TNC) and periostin (POSTN) have been shown to have a role in the lung metastatic niche of experimental breast cancer models [31].

2.2. Intravasation The intravasation process implies the active entry of tumor cells into the lumina of lymphatic or blood vessels. This is mediated by the earlier described acquired mechanisms of cytoskeletal remodeling and activation of ECM-modifying enzymes. Tumor-macrophage crosstalk also seems to play an important role in promoting breast tumor cell intravasation [12]. Additionally, tumor cells via a variety of signalings, mainly converging on the actions of Vascular Endothelial Growth Factors (VEGFs), stimulate neoangiogenesis within their local microenvironment to gain access to more nutrients and oxygen and to mechanically expand the primary niche [13]. Both lymphangiogenesis and angiogenesis are critical phenomena involved in cancer cell spread and they have been correlated with poor patient prognosis [14,15].

2.5. Micrometastasis formation Extravasated breast cancer cells need to create specific conditions in the foreign microenvironment to form micrometastases. In response to growth factors released by primary tumor cells into the circulation, several molecules [e.g. VEGF-A, placental growth factor (PlGF), TGF-β, serum amyloid A3 (SAA3)] are up-regulated at the future metastatic sites leading to the recruitment of bone marrow-derived hematopoietic progenitor cells. In addition to these cells, other cell types, including fibroblasts, myeloid and endothelial cells, express cytokines and 2

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malignancy in women with a previous breast cancer diagnosis, most likely due to the correlation between excess body weight and risk of developing different primary cancers in the general population. Indeed, a meta-analysis of thirteen prospective studies, five cohort and eight nested case-control studies evidenced that high BMI significantly increased risks of contralateral breast cancers as well as endometrial and colorectal second primary cancers [59]. In the adjuvant setting, the impact of BMI on the effectiveness of systemic treatments has been proposed as a possible mechanism for the higher relapse frequency and the reduced survival rate observed in the obese patient population [60]. There are several data showing that the benefits of chemotherapy and/ or endocrine therapy, especially aromatase inhibitors, were significantly lower in obese compared to thinner women [61–66], posing greater challenges in breast cancer patient care and disease management. Taken together, these data suggest a unique and aggressive biology of breast cancers associated with obesity that might be related to a tumor environment metabolically activated by adipose tissues. In the obesity conditions, white adipocytes undergo hypertrophy and hyperplasia which results in pathophysiologic changes, including elevated levels of free fatty acids (FFA) and triglycerides, increased blood glucose, and insulin resistance. Obese fat tissue also produces inflammatory cytokines [e.g. tumor necrosis factor alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), TGF-β] and factors called adipokines with important local and systemic functions. The release of these molecules may profoundly impact breast cancer progression through both a direct action on neoplastic epithelial cells and indirect effects on tumor microenvironment [60]. Among adipokines, leptin, whose circulating levels rise in proportion to BMI and the total amount of body fat stores, has been widely recognized as a key driver of the intricate network tying obesity and breast cancer. Indeed, different clinical trials have been conducted or are ongoing focusing on the evaluation of leptin levels as primary or secondary outcome measures in breast cancer patients after behavioral dietary and exercise intervention (http://www.clinicaltrials.gov). Details of these studies are included in Table 1 [67–74].

adhesive proteins important in establishing the pre-metastatic niche [32–34]. For instance, under hypoxic condition, enhanced expression of carbonic anhydrase IX in breast cancer cells induces Granulocytecolony stimulating factor (G-CSF) secretion, which stimulates the mobilization of MDSCs to premetastatic lungs and facilitates metastasis [35]. As a subsequent event in the metastatic cascade, tumor cells may engraft the niche to populate micrometastases. 2.6. Metastatic outgrowth After development of clinically undetectable micrometastases, breast cancer cells have to growth to form macroscopic metastases (micrometastatic to macrometastatic transition). Cell proliferation is not occurring with a specific temporal pattern because tumor cells seeding at distant organ sites may remain quiescent and evade immunity for several years until they are capable of progressing. This phenomenon, supported by the detection of disseminated tumor cells in the bone marrow of patients without clinical or histopathologic signs of metastatic disease [36–38], is known as metastatic latency. In mammary carcinoma cells, the state of dormancy has been correlated to an inability to engage the focal adhesion kinase, integrin β1, and Src signallings within host tissues [39–41]. More recently, Malladi et al. proposed that latency and evasion of competent cancer cells isolated from early stage human breast carcinomas is controlled by autocrine WNT inhibition [42]. Alterations in the tumour microenvironment can also trigger signalling pathways in dormant cells leading to their switch to metastatic growth [43–46]. A complex relationship between cellular dormancy and BCSC model has been proposed [11]. Metastases can be then a source of further dissemination to other tissues. 3. Obesity and breast cancer: epidemiological and mechanistic aspects In addition to intrinsic reprogramming mechanisms, tumor cells encounter several extrinsic factors important to drive breast cancer progression and metastasis development. Indeed, it has become increasingly clear that environmental factors, such as overweight and obesity, are likely to influence the incidence and the mortality of a large variety of malignancies, including those of the breast. This scenario is alarming, since obesity represents a recognized epidemic worldwide with the latest data available from the World Health Organization (WHO) showing that ˜ 40% and ˜ 15% of women are, respectively, overweight (body mass index, or BMI > 25 kg/m2) or obese (BMI = 30.0–34.9 kg/m2, grade I; 35.0–39.9 kg/m2, grade II; and ≥ 40 kg/m2, grade III). The Women’s Health Initiative Clinical Trial, enrolling 67 142 postmenopausal women with a median of 13 years of follow-up, revealed that women who were obese-grade I or obese-grades 2 + 3 had, respectively, 52% and 86% higher risk of developing breast cancer compared with women with normal BMI. Importantly, obesity grade 2 + 3 was associated with more advanced disease, including larger tumor size, lymph-node positivity and regional/distant stage after diagnosis [47]. Other studies showed that obesity was associated with larger tumors, positive lymph node status, metastasis development, shorter distant disease-free interval and overall survival [48–55] as well as with the most aggressive triple-negative breast tumor subtype [56,57]. Ewertz et al. analysing the association between BMI and breast cancer outcomes in the Danish Breast Cancer Cooperative Group (n = 53 816 women) revealed that obese women had 46% higher risk of developing distant metastases after 10-year follow-up compared with normal-weight women [58]. Women with elevated BMI also exhibited increased risk of dying from breast cancer [58]. Accordingly, a robust meta-analysis of 82 studies assessed a 41% and a 35% higher risk, respectively, of all-cause mortality and breast cancer-specific mortality for obese women compared to normal-weight counterparts [57]. In addition, obesity increased the incidence of a second primary

4. Role of leptin in breast cancer progression and metastasis Adipocyte derived-factor leptin, discovered in 1994, has been known as an essential regulator of appetite and energy balance homeostasis and afterwards it has emerged as one of the most important adipokine related to obesity-associated breast cancer. Leptin exerts its effects through the transmembrane leptin receptor (ObR), a member of the class I cytokine receptor family ubiquitously expressed in several tissues. ObR consists of six isoforms (ObRa, ObRb, ObRc, ObRd, ObRe and ObRf), that derive from alternative RNA splicing of the db gene and exhibit a common leptin-binding domain, but diverse intracellular motifs. The full-length long isoform, ObRb, is the only one containing the intracellular domain required for the leptin-induced JAK-STAT signaling activation and is considered as the functional receptor. In addition to JAK-STAT pathway, the binding of leptin to this receptor activates several equally important routes, including those involving insulin receptor substrates (IRS), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), protein kinase C (PKC), mitogen-activated protein kinases (MAPK), and Rho family GTPases, that modulate multiple hallmarks of cancer development and particularly affect several steps in the metastatic cascade [75,76]. Indeed, both clinical and experimental evidences have highlighted the involvement of leptin/ObR axis in breast cancer progression and metastasis. 4.1. Clinical evidences Increasing evidence indicates that higher circulating leptin concentrations and/or elevated expression of leptin and its receptor in tumors are positively associated with a more malignant cancer 3

4

An Exercise RCT Targeting African-American Women With Metabolic Syndrome and High Risk for Breast Cancer

Lifestyles Of Health And Sustainability for Breast Cancer Survivors

Effects of Diet and Exercise on Ductal Carcinoma in Situ (DCIS)

NCT02895178

NCT02224807

Breast Cancer WEight Loss Study (BWEL Study)

NCT02750826

NCT02103140

Phase II Study of Metformin for Reduction of Obesity-Associated Breast Cancer Risk

NCT02028221

Effect of a Low-Calorie Diet and/or Exercise Program on Risk Factors for Developing Breast Cancer in Overweight or Obese Postmenopausal Women

Dietary and Exercise Interventions in Reducing Side Effects in Patients With Stage IIIIa Breast Cancer Receiving Aromatase Inhibitors

NCT03953157

NCT00470119

Exergaming Intervention and Breast Cancer Biomarkers in Black Women

NCT02152462

Metformin and Omega-3 Fatty Acids in Woman With a History of Early Stage Breast Cancer

The Tetrad BMI, Leptin, Leptin/ Adiponectin (L/A) Ratio and CA-15-3 is a Reliable Biomarker of Breast Cancer

NCT01643148

NCT02278965

Title

Clinicaltrials.gov

Not Applicable

Not Applicable

Not Applicable

Not Applicable

Phase 1

Phase 3

Phase 2

Not applicable

Phase 2

Completed

Phase

[70,71]

[69]

[68]

[66,67]

Not available

Not available

[65]

Not available

Not available

[64]

Results

(continued on next page)

Eligibility criteria: female patients attending mammography (40-60 years). Primary outcome: body mass index (BMI), leptin, leptin/adiponectin ratio and cancer antigen (CA) 15-3. Secondary outcome: BMI. Eligibility criteria: sedentary (< 60 min/wk exercise) black women (40-59 years) with BMI ≥ 28 kg/m2 but ≤ 350 pounds of body weight, never been diagnosed with cancer. Primary outcome: leptin, adiponectin, Insulin-like growth factor 1 (IGF-1), Insulin-like growth factorbinding protein 3 (IGFBP3), C-reactive protein (CRP), Interleukin 6 (IL-6), insulin, c-peptide, and Hb-A1c levels. Secondary outcome: cardiovascular fitness, reported stressed levels. Eligibility criteria: female diagnosed with localized breast cancer, up to stage IIIa who has been taking aromatase inhibitor for at least six months, with at least 6 months post chemotherapy or radiation treatment; postmenopausal women, currently taking aromatase inhibitor medication. Primary outcome: bone mineral density, joint and muscle pain, grip strength; IL-6, IL-8, TNF-α, MCP-1, hs-CRP, leptin, TGF-β, IL-1 β, and CRP. Eligibility criteria: premenopausal women (21-54 years) having a BMI ≥ f 25 kg/m2 with no change in menstrual patterns for the past 6 months. Waist circumference ≥35 inches or ≥31 inches for Asian Americans, individuals with polycystic ovary syndrome, or with non-alcoholic fatty liver disease. Have at least one component of metabolic syndrome: triglycerides ≥ 150 mg/dL, HDL-C < 50 mg/dL, blood pressure (≥ 130 mmHg systolic or ≥85 mmHg diastolic), glucose ≥100 mg/dL; mammogram negative for breast cancer within the 12 months preceding the time of registration for women ≥ 50 years of age. Primary outcome: breast density. Secondary outcome: insulin, testosterone, IGF-2, IGF-1/IGFBP-3 ratio, leptin/adiponectin ratio, body weight, waist circumference. Eligibility criteria: female (> 18 years) with histologically confirmed invasive breast cancer; neoadjuvant subjects should have no evidence of clinical T4 disease prior to chemotherapy/surgery. No evidence of metastatic disease. Her-2 negative. BMI ≥ 27 kg/m2. Primary outcome: invasive disease-free survival. Secondary outcome: overall survival, distant disease-free survival, weight, measures of physical activity, dietary intake. Occurrence of insulin resistance syndrome complications, and insulin, glucose, leptin, adiponectin, IGF-1, IGFBP3, IL-6, CRP, TNF-α; physical functioning, fatigue, depression and anxiety, sleep disturbance, breast cancer treatment related symptoms. Eligibility criteria: stage 0, I, II, or III breast carcinoma patients (21-75 years). BMI ≥ 25 kg/m2 or baseline fasting glucose < 126 mg/dl. Primary outcome: number of participants successfully completing the 1-year intervention. Secondary outcome: reduction of mammographic density; insulin, glucose, C-peptide, leptin, adiponectin, IGF-1, IGFBP-1, total cholesterol, HDL, LDL; BMI and blood pressure. Eligibility criteria: postmenopausal female (50-75 years) at increased risk for developing breast cancer due to any of the following lifestyle risk factors: lack of physical activity, excess weight, obesity, weight gain over lifetime, BMI > 25. Primary outcome: estrone. Secondary outcome: estradiol, free estradiol, testosterone, free testosterone, sex hormone binding globulin; mammographic density; BMI; quality of life; insulin, glucose, IGF-1, Vitamin D, ghrelin, IL-6, adiponectin, and leptin. Eligibility criteria: African-American postmenopausal women (45-65 years) with waist circumference > 35 inches, 5-year invasive breast cancer risk > 1.40% (CARE model), having at least one of the following: glucose ≥100 mg/dL, blood pressure ≥ 130/85 mm/Hg. Primary outcome: waist circumference and BMI; IL-6, TNF-α, high sensitivity CRP, fasting glucose, insulin, IGF-1, IGFBP-3, leptin, adiponectin; metabolic syndrome. Secondary outcome: cardiorespiratory fitness, health-related quality of life. Eligibility criteria: breast cancer patients (18-64 years; stage I-III), undergone a lumpectomy or mastectomy, that have completed neoadjuvant/adjuvant chemotherapy and able to initiate exercise program; nonsmokers. Primary outcome: physical fitness components; anthropometric parameters. Secondary outcome: cancer-related molecules; adiponectin, leptin, myokines, inflammatoryrelated cytokines. Eligibility criteria: postmenopausal women (> 19 years) with intermediate-to-high nuclear grade DCIS or stage I or II breast cancer who elect surgery; overweight or obese (BMI: 25-60). Primary

Eligibility Criteria, Primary/Secondary Outcomes

Table 1 List of the studies on leptin and breast cancer evaluating leptin levels as serum biomarkers at http://www.clinicaltrial.gov/.

I. Barone, et al.

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outcome: tumor proliferation, weight. Secondary outcome: body composition, waist circumference, tumor markers on the CHIEF (Convergence of Hormonal, Inflammatory and Energyrelated Factors); pathway: Insulin Receptor, VEGF, TNF-α, Nuclear Factor Kappa Beta, caspase-3; insulin, leptin, Sex Hormone Binding Globulin; dietary intake, physical activity, quality of life, and cardiorespiratory fitness. Eligibility criteria: female (> 21 years) diagnosed with primary breast, cervical, endometrial or ovarian cancer (stage I-III). Completed treatment for breast cancer. Primary outcome: Hula program feasibility. Secondary outcome: sex hormones, cytokines, leptin, CRP, IGF-1, and IGFBP3; DNA methylation patterns; physical activity and health-related quality of life.

Not available

behavior. In postmenopausal ER-positive breast cancer patients, serum leptin levels were significantly higher in more advanced tumor stage (pT and TNM stage) and in the presence of distant metastases [77]. Accordingly, other two studies have reported that leptin concentrations were significantly associated with TNM staging, tumor size, histological grading, lymph node involvement and metastasis among postmenopausal breast cancer cases [78,79]. Interestingly, in obese patients with ER-positive breast cancer, Hosney et al. observed a statistically significant increase in the levels of leptin in plasma samples from the tumor microenvironment compared with peripheral plasma samples [80]. Moreover, it has been reported that an increased serum ratio of leptin/adiponectin in breast cancer patients was positively correlated with tumor size [81] as well as with lymph node metastasis [82]. Furthermore, recent meta-analyses indicated that leptin plays a potential role in breast cancer progression [83–86]. Expression of leptin and/or its receptor in breast cancer samples also correlates with tumor aggressiveness. In an initial study, Ishikawa and colleagues observed that patients with over-expression of ObR and leptin in primary breast tumors displayed enhanced occurrence of distant metastasis [87]. Consistently with these results, the expression of leptin and ObR, examined by immunohistochemistry in 148 primary breast cancers, 66 breast cancer metastases and in 90 benign mammary lesions, was significantly higher in primary and metastatic breast cancer than noncancer tissues [88]. Similarly, patients with breast cancer who had increased levels of ObR mRNA transcripts in their breast tumors, concomitant with elevated serum leptin levels, had a poorer prognosis compared to a subset of patients with low serum leptin or low intratumoral ObR mRNA levels [89]. Furthermore, in ER-negative breast cancer patients, ObR was found to be significantly overexpressed in metastatic lymph nodes as compared to primary tumors or lymph nodes from ER-positive patients [90]. Additionally, an univariate Cox analyses indicated that an elevated ObR-Long/ObR-Short ratio in breast tumors was associated with a shorter relapse-free survival [91] and, more recently, Kaplan-Meier survival analysis revealed that high ObR expression correlated with reduced overall survival in breast carcinoma patients, especially in those with basal-like subtypes [92].

Not Applicable

Phase

Eligibility Criteria, Primary/Secondary Outcomes

Results

I. Barone, et al.

Title

Hula, a Physical Activity Intervention for Female-Cancer Survivors

Clinicaltrials.gov

NCT02351479

Table 1 (continued)

4.2. Experimental evidences A growing body of evidence has raised the important role of leptin as an active player involved in breast cancer progression and metastasis by increasing cell migration and invasion, influencing EMT, remodeling ECM, predisposing cells toward the path of acquiring cancer stem celllike traits, impacting angiogenesis and modulating immune responses. 4.2.1. Leptin promotes breast tumor migration and invasiveness Several ‘in vitro’ experimental models have been extensively used to elucidate the molecular mechanisms of leptin-induced cell migration and invasion in breast cancer (Table 2) [92–112]. Huang et al. indicated that leptin enhances migration and invasion of MCF-7 and T47D breast cancer cells via an up-regulation of acetyl-CoA acetyltransferase 2 (ACAT2), an enzyme that is involved in the production of cholesteryl esters, through the PI3K/AKT/Sterol regulatory element-binding protein 2 (SREBP-2) signaling pathway [96]. In ER-α positive MCF-7 breast cancer cells, it has been reported that the multifunctional adaptor protein APPL1 (containing pleckstrin homology domain, phosphotyrosine binding domain, and a leucine zipper motif 1) may function as a binding partner of leptin receptor and STAT3 protein to promote leptininduced cell migration [99]. Leptin-dependent cell migration was also found to be mediated through a suppression of CCN5, a member of ECM-associated cysteine-rich protein family, by the activation of JAK/ Akt/STAT3-signaling [93]. Interestingly, Knight et al. identified an upstream leptin-EGFR-Notch1 axis in the regulation of survivin expression and migration of breast cancer cells [110] and Battle et al. underscored Notch signaling as an essential mediator of leptin-induced cell migration in an obesity context [105]. In addition, a crosstalk 5

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Table 2 ‘In vitro’ studies showing leptin effects on migration and invasion of breast cancer cells. Cell lines

Signaling molecules and pathways

Findings

References

MCF-7, ZR-75-1 MDA-MB-231, MDA-MB-468 E-Wnt and M-Wnt, MDA-MB-231

JAK/AKT/STAT

Leptin induces cell migration by suppressing CCN5 signaling

[90]

JAK/STAT3 and PI3K/Akt

Leptin stimulates cell migration via upregulation of PLOD2 expression

[91]

JAK/STAT3

Leptin enhances migration and invasion regulating the expression of Foxc2, Twist2, Vim, Akt3, and Sox2 genes Leptin promotes the migration and invasion by upregulating ACAT2 Leptin increases migration and invasion Leptin induces motility and invasion APPL1 sustains leptin signaling thus contributing cell migration Leptin, by stimulating IL-8 production in M2 macrophages, promotes migration and invasion Leptin promotes cell migration and invasion via IL-18 expression in both TAMs and MCF-7

[92]

obASC-derived leptin plays an important role in sustaining cell invasion

[99]

JAK2/STAT3/Akt and MAPK ERK Leptin-Notch ERK and Akt

Leptin Leptin Leptin Leptin

[100] [101] [102] [103]

JAK2/STAT3

CAF-derived leptin plays an important role in motility and invasion

[104]

Akt/GSK3 and MTA1/Wnt1 Notch, IL-1 and Leptin Leptin-EGFR-Notch1

Leptin induces migration and invasion by β-catenin activation Leptin induces migration and invasion Leptin induces migration and invasion by increasing survivin expression

[105] [106] [107]

JNK Leptin and IGF-I

Leptin stimulates invasion by MMP-2 Leptin promotes migration and invasion through EGFR transactivation

[108] [109]

MCF-7, MCF-7, MCF-7, MCF-7 MCF-7, MCF-7

T47D MCF10AT1 MDA-MB-231, SKBR3 MDA-MB-231

MCF-7, ZR75, T47D MCF-7, SKBR3 MCF-7 E0771, E0771-R218H MCF-7, T47D, MDA-MB-231, MDA-MB-468 MCF-7/SKBR3 YFP-WT ERα MCF-7/SKBR-3 YFP-K303R ERα MCF-7 4T1 cells MCF-7, MDA-MB-231 MCF-7 MCF-7, MDA-MB-231, MDA-MB-468

PI3K/Akt/SREBP-2 TGFB1 STAT3 STAT3, ERK1/2, and Akt p38 and ERK NF-κB/NF-κB1 in TAMs PI3K-AKT/ATF-2 in MCF-7 SERPINE1 and MMP-2

induces motility and invasion promotes the proliferation and migration induces migration induces migration and invasion

[93] [94] [95] [96] [97] [98]

Abbrevations: CCN5: Cellular Communication Network Factor 5; PLOD2: Procollagen-Lysine,2-Oxoglutarate 5-Dioxygenase 2, Vim: vimentin, ACAT2: Acetyl-CoA Acetyltransferase 2, APPL1: Adaptor Protein, Phosphotyrosine Interacting with PH Domain and Leucine Zipper 1, TAMs: Tumor-associated macrophages, obASC: obese adipose stromal cells.

elevation in cellular acetyl-CoA levels, increase in Smad2 transcription factor acetylation and activation and induction of EMT and metastasis [115]. A role for pyruvate kinase M2 (PKM2) in leptin-induced breast cancer cell EMT has also been shown [116], underscoring how metabolic reprogramming can directly impact EMT [117]. Recently, Sabol et al. demonstrated that leptin produced by obesity-altered adipose stem cells promotes EMT in triple-negative breast cancer cells through an increased expression of TWIST1, Serpine1, SNAI2, IL-6, and PTGS2 [118]. MMTV-Wnt-1 transgenic mice, which develop spontaneous basal-like, triple-negative mammary tumors, under a diet-induced obesity regimen (DIO mice) showed reduced survival, upregulated EMT gene signature, and increased leptin signaling versus mice receiving a control diet [95]. Interestingly, similar to breast adipocytes from obese women, adipocytes deficient for the tumor suppressor p16INK4A induced EMT in normal primary breast luminal cells in a leptin-dependent manner and promoted tumor growth [119].

between leptin and IGF-I signaling through epidermal growth factor receptor (EGFR) transactivation promotes the invasive and metastatic properties of breast cancer cells was reported [112], further highlighting the ability of leptin to interact with multiple oncogenic pathways. Moreover, the adipocyte-derived leptin was shown able to directly stimulate IL-18 expression in breast cancer cells through PI3K/ Akt/ATF-2 pathway activation, leading to invasion of breast cancer cells [101]. In another study, He et al. provided evidence that leptin along with IL-6 promotes breast cancer metastasis via upregulation of Lysyl Hydroxylase-2 expression through JAK/STAT3 and PI3K/Akt activation. They found that depletion of leptin receptor or treatment with an IL-6 blocking antibody abolished the adipocyte-induced dissemination of MDA-MB-231 breast cancer cells toward the lungs and significantly decreased both the size and number of the metastatic nodules [94]. In the MMTV-PyMT (mouse mammary tumor virus-polyoma virus middle T antigen) mammary tumor model of breast cancer, Park et al. observed that an absence of ObR attenuated tumor progression and lung metastasis through a reduction of ERK1/2 and JAK2/STAT3 pathways [113].

4.2.3. Leptin affects MMP activities A possible association between leptin and tumor metastatic potential via activation of MMPs has been reported. Leptin is able to increase in a dose-dependent manner the secretion of different MMPs, such as MMP-2 and MMP-9, in cultured human cytotrophoblastic cells [120], murine cardiomyocytes [121], and in human umbilical vein endothelial cells [122]. In line with these results, it was demonstrated that leptin regulates the expression of many MMPs in several kind of cancers [123–125], including breast carcinomas. In particular, leptin-induced Jun N-terminal kinase (JNK) activation is associated with enhanced MMP-2 activity and invasion of ER-positive breast cancer cells [111]. It was also shown that obese adipose stromal cells not only support primary breast tumor growth, but they also promote metastasis through a leptin-mediated signaling pathway(s) involving MMP-2 [102]. Indeed, leptin knockdown in stromal cells significantly decreased tumor burden

4.2.2. Leptin stimulates EMT Different studies have shown that leptin may promote EMT, and a number of mechanisms have been proposed. For example, a potential cross-talk between leptin and MTA1/Wnt signaling in EMT has been reported in breast cancer cell lines [108]. Leptin-mediated IL-8 activation via phosphorylation of intracellular signaling molecules, including STAT3, AKT, and ERK1/2, stimulated breast cancer cells to undergo EMT [114]. Exposure of MCF-7 cells to leptin treatment resulted in a marked increase in the expression of mesenchymal markers (vimentin and snail) along with a down-regulation in the epithelial marker E-cadherin and these effects can be impaired by co-treatment with CCN5 protein [93]. Moreover, leptin and TGF-β treatments led to 6

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angiogenic actions could involve both short-term effects via a direct transactivation of VEGFR-2 in endothelial cells as well as long-term effects mediated by the upregulation of MMPs, integrins and NILCO in breast cancer cells, which in turn induces VEGF/VEGFR-2 expression [137]. In addition, leptin could also cause the proliferation of fibroblasts and attract macrophages along with other inflammatory cells within the tumor microenvironment, reinforcing angiogenesis via crosstalk with several cytokine/growth factor signalings [137,138].

and reduced the number of metastatic lesions to the lung and liver of SCID/beige mice and this correlated with reduced MMP-2 levels. A robust influence of leptin on ECM genes, including Connective Tissue Growth Factor, Villin 2 and Basigin, has also been demonstrated in MCF-7 breast cancer cells [126], further highlighting the ability of leptin to drive changes in the expression of key metastatic factors within a tumor. 4.2.4. Leptin supports BCSC survival The aggressive features of certain solid tumors are considered to result, at least in part, from the expansion of CSC populations with selfrenewal and differentiation abilities that ultimately may lead to tumor heterogeneity, invasion, metastasis, drug resistance, and disease recurrence [11]. During the last ten years, the role of leptin in this context has also been well described. One of the first evidence to indicate the involvement of this adipokine in BCSC enrichment was from ‘in vivo’ limiting dilution analysis of residual tumors from leptin-deficient mice, that showed reduced CSC potential compared to those from wild-type mice [127]. In subsequent studies, activation of ObR signaling was reported to be essential for maintaining CSC-like and metastatic properties in triple-negative breast cancers [128,129]. Interestingly, DIO mice versus control exhibited upregulated CSC gene signature and increased tumoral aldehyde dehydrogenase enzymatic activity, a wellknown CSC marker [95]. An elegant report of Chang and colleagues showed that leptin promoted a CSC phenotype in normal and malignant human epithelial breast cells [130]. In particular, leptin, through STAT3 signaling activation, was able to recruit G9a histone methyltransferase, causing a repression of miR-200c by epigenetic silencing, which in turn stimulated the formation of BCSCs. Inhibiting STAT3/G9a pathway restored expression of miR-200c, thus reversing the CSC phenotype. Moreover, the authors reported, in a diet-induced obesity rat model of breast cancer, that STAT3 blockade significantly reduced the tumor sphere-forming capacity and abrogated tumor growth, highlighting how targeting STAT3-G9a signaling may regulate CSC plasticity in obesity-related breast cancer [130]. Moreover, Wang et al. identified a novel leptin-ObR-JAK-STAT3-dependent FAO (fatty acid βoxidation) signaling as critical for BCSC self-renewal and chemoresistance. Indeed, targeting FAO and/or leptin pathways resensitizes cancer cells to chemotherapy and inhibited breast cancer stemness ‘in vivo’ [17]. We have also reported that leptin, acting as a mediator of the interaction between tumor and stroma cells (adipocytes and cancer associated fibroblasts), may impact BCSC activity using patient-derived samples and breast cancer cell lines [92]. Recently, TGFB1 and its own receptor were shown as a functionally important and novel pathway able to mediate the action of leptin in promoting metastasis and stemness, further strengthening the contribution of activated leptin signalling to poorer breast cancer outcomes in obesity [97].

4.2.6. Leptin influences immune responses Leptin has been known to regulate the immune response through targeting immune cells [139], an effect that is involved in supporting indirectly cancer progression. Leptin receptor ObRb has been found to be expressed in various immune cell types, including different subpopulations of T cells, B cells, dendritic cells, monocytes, neutrophils, NK cells, and macrophages and this cells may respond to leptin stimulation by secreting pro-inflammatory and pro-angiogenetic cytokines (i.e. IL-1, IL-6 and TNF-α) [140–147]. In addition, leptin, through canonical ObR signaling activation, acts as a potent inducers of monocyte/macrophage motility and chemotaxis [148]. ‘In vivo’ experiments demonstrated that adipose tissue within the mammary tumor microenvironment of obese mice exhibited higher numbers of macrophages and crown-like structures (CLS) than that of lean tumor-bearers [147]. Recently, it was shown that leptin promoted breast cancer cell invasion and metastasis by stimulating IL-18 expression via ObR, NF-κB and NF-κB1 in tumor-associated macrophages [101]; while Cao et al. demonstrated that leptin treatment indirectly stimulated breast cancer progression through an induction of ObR expression and IL-8 production mediated by MAPK/ERK1/2 and P38/MAPK pathways in M2 macrophages [100]. Accordingly, in nude mice xenograft models treatment with leptin significantly increased tumor volume and lung metastasis that were reduced by macrophage depletion as well as by injection of anti-mouse IL-8 neutralizing antibodies [100]. Thus, leptin/ ObR/IL signalings within the tumor microenvironment may represent additional mechanisms linking obesity to breast carcinogenesis. 5. Conclusions & future areas of research The increase in global burden of obesity, especially in developing countries undergoing rapid socio-economic changes, has been intricately associated with breast cancer risk and progression. Indeed, adipose tissue, traditionally considered only as an energy store, is nowadays recognized as endocrine organ that plays a key role in the pathogenesis of several diseases, including mammary carcinomas. The tumor promoting functions of dysfunctional adipocytes are a result of both systemic actions and local effects within tumor microenvironment mediated by a variety of active molecules, such as leptin. This adipokine has long been woven with breast tumour development and growth and over the last years, it has been recognized as a factor able to orchestrate several pathways involved in the steps of the invasion-metastasis cascade. Indeed, leptin can favor the metastatic behaviour of breast tumours via effects on EMT, MMP activities, breast CSC survival, angiogenesis and tumor-immune cell crosstalk (Fig. 1). Thus, the signalings triggered by leptin can function as valuable pharmacological targets to develop more effective anti-cancer treatments and should be further explored. However, in spite of these findings, many other issues remain still to be clarified. Does leptin affect tumor dormancy? May leptin influence CTC survival? May leptin contribute to promote the formation of pre-metastatic niches? May leptin contribute to influence systemically organs for future metastasis? Answering these questions will lead to a more comprehensive understanding of the mechanisms underlying the obesity-leptin-breast cancer connection and will be instrumental to reveal novel markers and targets for disease management. In the meantime, lifestyle interventions (e.g. weight loss and exercise) need to be considered as strategies for prevention and survival improvement for breast cancer patients.

4.2.5. Leptin induces angiogenesis Adipocytes actively participate in angiogenic modulation through the secretion of adipokines, including leptin [131]. Indeed, studies demonstrated that leptin can induce, in a paracrine manner, activation, proliferation and migration of endothelial cells expressing ObR [132–134]. Furthermore, leptin synergistically stimulates blood-vessel growth in cooperation with VEGF and fibroblast growth factor (FGF) 2, the two most potent and frequently expressed angiogenic molecules [135]. It was also reported that leptin signaling induced VEGF expression in breast cancer via HIF-1α (Hypoxia-inducible factor 1-alpha) and NFκB; thus providing an additional advantage to cancer cells under hypoxia [136]. In mouse (4T1, EMT6 and MMT) mammary cancer cell lines, treatment with leptin promoted cell proliferation and migration, as well as upregulation of VEGF and its receptor VEGFR-2 [109]. This is highly dependent of the Notch, IL-1, and leptin cross talk outcome (NILCO) in breast cancer, thus proposing NILCO as an integration of signalings critical for leptin-induced breast cancer progression, tumor angiogenesis and stemness [109]. Molecular mechanisms of leptin pro7

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Fig. 1. The potential role of the adipocyte-derive leptin on the metastatic cascade in breast cancer. Obese dysfunctional adipocytes, distant from tumor and present within the tumor microenvironment, produce high levels of leptin that strongly contribute to breast cancer progression. Indeed, leptin binds to its own receptor expressed in neoplastic cells and stromal components, including immune cells, endothelial cells and cancer-associated fibroblasts, and activates multiple signalling pathways, which in turn may lead to an increased cell migration and invasion, Epithelial-Mesenchymal Transition (EMT), Matrix Metalloproteinase (MMP) activity, Breast Cancer Stem Cell (BCSC) formation and maintenance, angiogenesis and recruitment of immune cells. All these effects stimulate the entry of invasive cells into the circulation and the subsequent metastatic colonization of distant organs, such as bone, lung, liver and brain.

Review criteria

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A search for original articles published between 1998 and 2019 was performed in PubMed. The search terms used were ‘breast cancer metastasis’, ‘obesity and breast cancer’, ‘leptin and breast cancer’, ‘leptin and breast cancer metastasis’, ‘leptin and breast cancer migration’, ‘leptin and breast cancer invasion’, ‘leptin and EMT’, ‘leptin and MMP’, ‘leptin and breast cancer stem cells’, ‘leptin and angiogenesis’, ‘leptin and immunity’, ‘leptin and dormancy’, ‘leptin and metastatic latency’, ‘leptin and circutating tumor cells’, ‘leptin and pre-metastatic niches’, ‘leptin and breast cancer tropism’. All articles selected were Englishlanguage, full-text papers. We also identified further relevant articles from the reference lists of selected papers. Declaration of Competing Interest The authors declare that there are no conflicts of interest. Acknowledgments This work was supported by Fondazione Italiana per la Ricerca sul Cancro – AIRC: IG 11595 to S. Andò, MFAG#16899 to I. Barone and IG #21414 to S. Catalano. References [1] F. Cardoso, A. Costa, L. Norton, D. Cameron, T. Cufer, L. Fallowfield, et al., 1st international consensus guidelines for advanced breast cancer (ABC1), Breast 21 (3) (2012) 242–252. [2] Early Breast Cancer Trialists’ Collaborative G, R. Peto, C. Davies, J. Godwin, R. Gray, H.C. Pan, et al., Comparisons between different polychemotherapy regimens for early breast cancer: meta-analyses of long-term outcome among 100,000 women in 123 randomised trials, Lancet 379 (9814) (2012) 432–444. [3] S. Paget, The distribution of secondary growths in cancer of the breast. 1889, Cancer Metastasis Rev. 8 (2) (1989) 98–101.

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