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Using in vitro and in vivo models, the study mimics the obesity microenvironment with pro-inflammatory cytokines plus adipokines, showing epithelial-to-mesenchymal transformation and cancer hallmarks. 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Excess energy stored in adipocytes can lead to adipose tissue dysfunction and chronic low-grade inflammation that supports carcinogenic processes.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"What experimental approach was used to study the obesity microenvironment?",{"text":68,"@type":64},"The study used both in vitro and in vivo approaches. It cultured cells in enriched pro-inflammatory cytokine media with added low concentrations of beneficial adipokines, and validated findings using high-fat-diet-fed mice.",{"name":70,"@type":61,"acceptedAnswer":71},"What role does RhoJ play in breast cancer development in the proposed mechanism?",{"text":72,"@type":64},"Transcriptomic analysis highlighted RhoJ as a potential molecular driver in obese breast tissues. 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Bou Malhab 1,*, Vidhya A. Nair 1, Rizwan Qaisar 2, Gianfranco Pintus 3 and  \nWael M. Abdel-Rahman 1,4, *  \nCitation: Bou Malhab, L.J.; Nair, V.A.; Qaisar, R.; Pintus, G.; Abdel-Rahman, W.M. Towards Understanding the Development of Breast Cancer: The Role of RhoJ in the Obesity Microenvironment. Cells 2024, 13, 174 . [https://doi.org/10.3390/cells13020174](https://doi.org/10.3390/cells13020174)  \nAcademic Editors: Tiziana Triulzi and Marilena V. Iorio  \nReceived: 25 October 2023  \nRevised: 21 December 2023  \nAccepted: 4 January 2024  \nPublished: 17 January 2024  \nCopyright: © 2024 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ([https://](https://)[ ](https://)[creativecommons.org/licenses/by/](creativecommons.org/licenses/by/)[ ](creativecommons.org/licenses/by/)[4.0/](4.0/)) .  \n1 Research Institute of Medical and Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates; [vnair@sharjah.ac.ae](vnair@sharjah.ac.ae)  \n2 Basic Medical Sciences, College of Medicine, University of Sharjah, Sharjah 27272, United Arab Emirates; [rqaisar@sharjah.ac.ae](rqaisar@sharjah.ac.ae)  \n3 Department of Biomedical Sciences, University of Sassari, 07100 Sassari, Italy; gpintus@uniss.it  \n4 Department of Medical Laboratory Sciences, College of Health Sciences, University of Sharjah, Sharjah 27272, United Arab Emirates  \n* Correspondence: [lbonmalhab@sharjah.ac.ae](lbonmalhab@sharjah.ac.ae) (L.J.B.M.); [whassan@sharjah.ac.ae](whassan@sharjah.ac.ae) (W.M.A.-R.)  \nAbstract: Obesity is a growing pandemic with an increasing risk of inducing different cancer types, including breast cancer. Adipose tissue is proposed to be a major player in the initiation and progression of breast cancer in obese people. However, the mechanistic link between adipogenicity and tumorigenicity in breast tissues is poorly understood. We used in vitro and in vivo approaches to investigate the mechanistic relationship between obesity and the onset and progression of breast cancer. In obesity, adipose tissue expansion and remodeling are associated with increased inflammatory mediator’s release and anti-inflammatory mediators’ reduction.. In order to mimic the obesity micro-environment, we cultured cells in an enriched pro-inflammatory cytokine medium to which we added a low concentration of beneficial adipokines. Epithelial cells exposed to the obesity microenvironment were phenotypically transformed into mesenchymal-like cells, characterized by an increase in different mesenchymal markers and the acquisition of the major hallmarks of cancerous cells; these include sustained DNA damage, the activation of the ATR-Chk2 pathway, an increase in proliferation rate, cell invasion, and resistance to conventional chemotherapy. Transcriptomic analysis revealed that several genes, including RhoJ, CCL7, and MMP9, acted as potential major players in the observed phenomenon. The transcriptomics findings were confirmed in vitro using qRT-PCR and in vivo using high-fat-diet-fed mice. Our data suggests RhoJ as a potential novel molecular driver of tumor development in breast tissues and a mediator of cell resistance to conventional chemotherapy through PAK1 activation. These data propose that RhoJ is a potential target for therapeutic interventions in obese breast cancer patients.  \nKeywords: breast cancer; chronic inflammation; obesity; RhoJ; tumor micro-environment  \n1. Introduction  \nObesity has become a worldwide concern because of its impact on public health. By 2025, global obesity prevalence is expected to reach 18% in men and more than 21% in women [1] . Obesity is an excess of body fat, considered to be harmful to health and defined by the World Health Organization (WHO) as a body mass index (BMI) (b","cbCaifbshGbfWpzC","https://ap.wps.com/l/cbCaifbshGbfWpzC","pdf",3212667,24,"English","# 1. Introduction\n## Obesity as a public health concern and cancer risk factor\n## Breast cancer carcinogenesis and adipose tissue contributions","[{\"question\":\"How does obesity contribute to breast cancer risk according to the document?\",\"answer\":\"Obesity increases the risk of several cancer types, including breast cancer. Excess energy stored in adipocytes can lead to adipose tissue dysfunction and chronic low-grade inflammation that supports carcinogenic processes.\"},{\"question\":\"What experimental approach was used to study the obesity microenvironment?\",\"answer\":\"The study used both in vitro and in vivo approaches. It cultured cells in enriched pro-inflammatory cytokine media with added low concentrations of beneficial adipokines, and validated findings using high-fat-diet-fed mice.\"},{\"question\":\"What role does RhoJ play in breast cancer development in the proposed mechanism?\",\"answer\":\"Transcriptomic analysis highlighted RhoJ as a potential molecular driver in obese breast tissues. The data suggest RhoJ mediates resistance to conventional chemotherapy through PAK1 activation.\"}]","Towards Understanding the Development of Breast Cancer - The Role of RhoJ in the Obesity Microenvironment | PDF",1789975318]