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    • The presence of crown like structures and inflammatory facto

    2023-05-29

    The presence of crown-like structures and inflammatory factors in the breast of obese patients is associated with considerable changes in intracellular signaling and a profound cellular dysfunction. Secreted pro-inflammatory factors can directly promote breast carcinogenesis as they have been reported to induce cell proliferation, cancer cell invasion and metastasis (van Kruijsdijk et al., 2009). More importantly, these inflammatory factors are at the origin of the switch of promoter use occurring in breast adipose stromal APETx2 of obese patients leading to elevated aromatase expression and increase of estrogen production, which in turn, promotes breast epithelial cell proliferation, leading to cancer promotion (Fig. 1). The shift in aromatase promoter use from PI.4 to more potent PI.3/II accounts for the elevated aromatase expression and enhanced in situ estrogen biosynthesis observed in the breast of obese postmenopausal women (To et al., 2015). As a result of the promoter switch, the regulation of estrogen production changes from one controlled primarily by glucocorticoids and cytokines to a regulation controlled by inflammatory factors. Some studies have confirmed predominance of PI.3/II usage over PI.4 in breast cancer tissues (Agarwal et al, 1996, Zhou et al, 1996). In addition to an increase in total aromatase mRNA levels in tumor tissue compared to breast normal tissue in a study conducted on 108 female samples, Irahara et al. reported that the percentage of promoter I.4 usage was significantly lower in tumor tissue than in normal breast tissue (Irahara et al., 2006). On the other hand, the percentage of promoter I.3 and II usage gradually and significantly increased from axillary adipose tissue, mammary adipose tissue and normal breast tissue adjacent to tumor tissue. Moreover, histological grade III was associated with significantly higher usage of promoter I.3 than those of histological grades I and II (Irahara et al., 2006). The regulation of this shift of aromatase promoter usage in adipose stromal cells is complex and is still under investigation. The next sections will present some of the key findings and recent discoveries regarding molecular mechanisms linking the best-known obesity-related factors (PGE2, IGF-1, leptin and adiponectin) and dysregulated aromatase expression/estrogen signaling.
    There is strong evidence for the hypothesis that cyclooxygenase-2 (COX-2)-dependent signaling plays an important role in the obesity-breast cancer link via multiple mechanisms, including via the stimulation of aromatase expression and the local production of estrogens (Hugo et al, 2015, Bowers and deGraffenried, 2015). COX is an enzyme able to convert arachidonic acid to cyclic endoperoxidases (prostaglandin G2 and prostaglandin H2), which can be in turn converted to prostaglandins I2, D2 and E2 and thromboxane via their respective synthases (Hemler and Lands, 1976, Hemler and Lands, 1977). The inducible form of COX, termed COX-2, participates specifically in inflammation and has a central role in inflammation-driven cancers (Harris et al., 2014). Prostaglandin E2 (PGE2) acts mainly on the nervous system to produce sensitivity and pain at sites of inflammation. PGE2 also has an impact on the vascular system by causing dilatation and permeability of blood vessels, as well as exhibiting strong angiogenic properties (Ghosh, 2003). In the case of mammary tissue, COX-2 expression is highly expressed in breast tumors, not in normal breast tissue, and its expression is correlated to poor prognosis (Jana et al, 2012, Jana et al, 2014, Gawthorpe et al, 2014, Park et al, 2012). Interestingly, in the study conducted by Ristimaki and colleagues, the association of COX-2 expression with an unfavorable outcome was especially apparent in the subgroups defined by ER positivity (Ristimaki et al., 2002). However, a number of epidemiological breast cancer studies have shown no correlation or an inverse relationship between ER and COX-2 expression (Sun et al, 2014, Nassar et al, 2007). For example, using a tissue microarray, Zerkowski and colleagues have showed that COX-2 expression appeared higher in malignant than in benign tissue and was correlated to a lower survival rate but was inversely associated with ER expression (Zerkowski et al., 2007). These divergences suggest that no clear conclusion can currently be made about the association of ER and COX-2 expression in breast cancer. However, the ER-COX-2 relationship may be influenced by the stage of the disease. APETx2 Cancer cells can lose their epithelial characteristics as they increase their migratory and invasive capacities. At a molecular level, overexpression of COX-2 is a characteristic feature of this epithelial-to-mesenchymal transition and the acquisition of a metastatic phenotype includes the loss of ER expression (Scherbakov et al., 2012).