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  • Knowledge about adipose tissue has evolved considerably

    2022-12-01

    Knowledge about adipose tissue has evolved considerably over the last two decades. Always been described as an inert tissue having the function of stocking lipids, adipose tissue is now recognized as a real organ with both metabolic and endocrine functions secreting various factors into the blood to interact with distal tissues and organs (Kershaw and Flier, 2004, Dizdar and Alyamac, 2004, Poulos et al., 2010). These factors, collectively called adipokines, play key metabolic functions and are able to modulate a variety of physiological responses such as the metabolism of lipids and glucose, satiety, inflammation, angiogenesis and homeostasis (Khan and Joseph, 2014). Dysregulation of the endocrine function of the adipose tissue and disturbed expression profile of adipokines, typical features of obese state, intimately connect obesity and breast cancer (Lafontan, 2014, O'Flanagan et al., 2015, de Ferranti and Mozaffarian, 2008). Chronic inflammatory condition associated with increased adiposity promotes the development and progression of postmenopausal breast cancer through numerous complex mechanisms, including through induction of aromatase expression and consequently of CGP 55845 hydrochloride synthesis production, a major mediator of breast carcinogenesis (Iyengar et al., 2013). The obesity-inflammation-estrogen axis forms a complex network of molecular players and interconnected signaling pathways by which the obese state impacts the risk of breast cancer in postmenopausal women. Given that obesity has reached epidemic proportions, understanding the mechanisms linking obesity and risk of breast cancer is of public health interest and is therefore important for cancer prevention efforts worldwide. This review will examine the inflammatory processes ongoing in adipose tissue and how this inflammatory environment can lead to breast carcinogenesis by driving changes in aromatase expression and endogenous estrogen production in breast of obese patients. A special attention will be given to key biological mechanisms underlying the impact of obesity on estrogen signaling in postmenopausal women. We will also highlight different therapeutic approaches that can be proposed to reduce the impact of obesity toward breast cancer.
    Estrogen: the fuel supporting hormone-dependent breast cancers Breast cancer is a complex and heterogeneous disease that can be divided into different subtypes depending on the pattern of expression of various markers, including steroid hormone receptors and human epidermal growth factor receptor 2 (HER2) (Malhotra et al, 2010, Taherian-Fard et al., 2015). This molecular classification is routinely used to categorize patients with breast cancer in order to assess prognosis and determine the appropriate therapy (Kast et al, 2015, Guerrero-Zotano et al, 2009, Dai et al, 2016). More than 75% of breast tumors express the estrogen receptor (ER), suggesting that the vast majority of breast cancers are hormone-dependent and grow in response to the hormone estrogen (Geyer et al., 2012). The estrogen estradiol (E2), through actions on its receptor, plays a crucial role in reproduction and normal physiology. Notably, E2 is essential for the development of normal breast epithelium by coordinating postnatal epithelial cell proliferation and ductal morphogenesis (Brisken and O'Malley, 2010). However, a large body of experimental and clinical research has also established the fundamental role of E2 and its receptor in the etiology and progression of breast cancer (Huang et al., 2015, Reznikov, 2015). E2-activated ER is a key regulator of breast carcinogenesis by driving complex biological pathways that control a variety of cell functions, such as growth, apoptosis, migration and angiogenesis (Gerard et al, 2015, Manavathi et al, 2013, Pesiri et al, 2014). Surprisingly, E2 has also been shown to increase the growth of ER-negative breast cancer cells. An in vivo study has demonstrated that E2 indirectly potentiates the growth of 4T1 mouse ER-negative breast tumor cell line subcutaneously grafted into mice by impacting tumor microenvironment (Pequeux et al., 2012). E2 was shown to increase intra-tumor vessel density, and modify tumor vasculature into a more regularly organized structure, thereby improving vessel stabilization to prevent tumor hypoxia and necrosis. These E2-induced effects were completely abrogated in ER-deficient mice, showing a critical role for ER in the tumor microenvironment (Pequeux et al., 2012).