Breast cancers (BCs) typically express estrogen receptors (ERs) but frequently exhibit de novo or acquired resistance to hormonal therapies. Here, we show that short-term treatment with the ...anti-estrogens tamoxifen or fulvestrant decrease cell proliferation but increase BC stem cell (BCSC) activity through JAG1-NOTCH4 receptor activation both in patient-derived samples and xenograft (PDX) tumors. In support of this mechanism, we demonstrate that high ALDH1 predicts resistance in women treated with tamoxifen and that a NOTCH4/HES/HEY gene signature predicts for a poor response/prognosis in 2 ER+ patient cohorts. Targeting of NOTCH4 reverses the increase in Notch and BCSC activity induced by anti-estrogens. Importantly, in PDX tumors with acquired tamoxifen resistance, NOTCH4 inhibition reduced BCSC activity. Thus, we establish that BCSC and NOTCH4 activities predict both de novo and acquired tamoxifen resistance and that combining endocrine therapy with targeting JAG1-NOTCH4 overcomes resistance in human breast cancers.
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•Anti-estrogen therapies selectively enrich for BCSCs and activate Notch signaling•Notch pathway activation and ALDH1 predict for anti-estrogen treatment failure•Targeting of Notch4 reduces the population of BCSCs•Notch inhibitors might prevent relapse or overcome resistance in ER+ tumors
Breast cancers frequently develop resistance to anti-estrogen treatment, which makes it imperative to understanding how therapy resistance develops. Here, Simões et al. show that combining standard anti-estrogen therapies with anti-Notch4 drugs targeting breast cancer stem cells should improve treatment of ER+ breast cancer patients by preventing relapse due to therapy resistance.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Adipose-tissue-derived signaling molecules, including the adipokines, are emerging as key candidate molecules that link obesity with cancer. Peritumoral, stromal, adipose tissue and secreted ...adipokines, particularly leptin, have important roles in breast cancer biology. For example, leptin signaling contributes to the metabolic features associated with breast cancer malignancy, such as switching the cells' energy balance from mitochondrial β-oxidation to the aerobic glycolytic pathway. Leptin also shapes the tumor microenvironment, mainly through its ability to potentiate both migration of endothelial cells and angiogenesis, and to sustain the recruitment of macrophages and monocytes, which in turn secrete vascular endothelial growth factor and proinflammatory cytokines. This article presents an overview of current knowledge on the involvement of leptin in the pathogenesis and progression of breast cancer, highlighted by human, in vitro and animal studies. Data are presented on the functional crosstalk between leptin and estrogen signaling, which further contributes to promotion of breast carcinogenesis. Finally, future perspectives and clinical applications in which leptin and the leptin receptor are considered as potential therapeutic targets for breast cancer are reviewed.
An efficient tumor-targeted niosomal delivery system for the vehiculation of doxorubicin hydrochloride as an anticancer agent was designed. Niosomes were prepared from a mixture of an opportunely ...modified Pluronic L64 surfactant and cholesterol as a membrane additive and characterized in terms of size and related distribution function and drug entrapment efficiency. After the preparation, transferrin was conjugated to niosomes to produce transferrin (Tf) niosomes, and the cytotoxicity of the final formulation was studied. The specific uptake of Tf niosomes into cells was evaluated via incubation of MCF-7 and MDA-MB-231 cells with fluorescently rhodamine-loaded Tf niosomes for various times and concentration intervals and further investigated by fluorescence microscopy. Results showed that doxorubicin can be easily encapsulated into niosomes, which are regular and spherical in shape. Moreover, transferrin conjugate niosomes demonstrated far greater extents of cellular uptake by MCF-7 and MDA-MB-231 cells, suggesting that they were mainly taken up by transferrin receptor-mediated endocytosis. Doxorubicin-loaded niosome anticancer activity was also achieved against MCF-7 and MDA-MB-231 tumor cell lines, and a significant reduction in viability in a dose- and time-related manner was observed. Finally, our formulation could be potentially useful as a target doxorubicin delivery system in anticancer therapy.
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IJS, KILJ, NUK, PNG, UL, UM
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.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Obesity, characterized by excess body weight, is now accepted as a hazardous health condition and an oncogenic factor. In different epidemiological studies obesity has been described as a risk factor ...in several malignancies. Some biological mechanisms that orchestrate obesity-cancer interaction have been discovered, although others are still not completely understood. The unbalanced secretion of biomolecules, called "adipokines", released by adipocytes strongly influences obesity-related cancer development. Among these adipokines, adiponectin exerts a critical role. Physiologically adiponectin governs glucose levels and lipid metabolism and is fundamental in the reproductive system. Low adiponectin circulating levels have been found in obese patients, in which its protective effects were lost. In this review, we summarize the epidemiological, in vivo and in vitro data in order to highlight how adiponectin may affect obesity-associated female cancers.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Summary
The incidence of obesity, a recognized risk factor for various metabolic and chronic diseases, including numerous types of cancers, has risen dramatically over the recent decades worldwide. ...To date, convincing research in this area has painted a complex picture about the adverse impact of high body adiposity on breast cancer onset and progression. However, an emerging but overlooked issue of clinical significance is the limited efficacy of the conventional endocrine therapies with selective estrogen receptor modulators (SERMs) or degraders (SERDs) and aromatase inhibitors (AIs) in patients affected by breast cancer and obesity. The mechanisms behind the interplay between obesity and endocrine therapy resistance are likely to be multifactorial. Therefore, what have we actually learned during these years and which are the main challenges in the field? In this review, we will critically discuss the epidemiological evidence linking obesity to endocrine therapeutic responses and we will outline the molecular players involved in this harmful connection. Given the escalating global epidemic of obesity, advances in understanding this critical node will offer new precision medicine‐based therapeutic interventions and more appropriate dosing schedule for treating patients affected by obesity and with breast tumors resistant to endocrine therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Highlights • Obesity is a pandemic condition associated with both risk and prognosis of breast cancer. • The adipokine leptin is a plausible molecular link between obesity and breast cancer. • Leptin ...signalling plays a critical role in breast cancer development and progression. • Leptin emerges as an attractive therapeutic target for prevention and treatment of breast cancer.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
We hereby apply the approach of photoacoustic chemical imaging, performing an in vivo chemical analysis that is spatially resolved (200 μm) and in real time, to predict a given tumor’s response to ...therapy. Using triple negative breast cancer as a model, we took photoacoustic images of tumors’ oxygen distributions in patient-derived xenografts (PDXs) in mice using biocompatible, oxygen-sensitive tumor-targeted chemical contrast nanoelements (nanosonophores), which function as contrast agents for photoacoustic imaging. Following radiation therapy, we established a quantitatively significant correlation between the spatial distribution of the initial oxygen levels in the tumor and its spatial distribution of the therapy’s efficacy: the lower the local oxygen, the lower the local radiation therapy efficacy. We thus provide a simple, noninvasive, and inexpensive method to both predict the efficacy of radiation therapy for a given tumor and identify treatment-resistant regions within the tumor’s microenvironment.
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IJS, KILJ, NUK, PNG, UL, UM
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