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  • Since obesity appears to impact leptin and adiponectin

    2024-04-02

    Since obesity appears to impact leptin and adiponectin levels in opposite manners, several studies have suggested that the serum adiponectin/leptin ratio may be a key parameter in indicating the relative risk of postmenopausal breast cancer (Ollberding et al, 2013, Cleary et al, 2009). Therapeutic strategies aiming at altering this ratio with inhibition of pro-neoplastic leptin pathways and reactivation of anti-neoplastic effects of adiponectin may benefit obese breast cancer patients (Surmacz, 2013).
    Possible therapeutic approaches Following the saying “prevention is better than cure” and given the potentially reversible nature of obesity, weight loss is one of the most intuitive and effective approaches to reduce the risk of breast cancer in the obese population. Some animal studies have shown that caloric restriction leads to decreased growth (up to 20-fold volume reduction) of chemically induced mammary tumors via a reduction in the tumor cell proliferation index and an increase of apoptosis (Zhu et al., 1999). A study conducted by De Lorenzo et al., highlighted that caloric restriction not only reduced the primary tumor size but also the number and size of metastases, suggesting that the mechanisms responsible for the spread and growth of spontaneous metastases may be inhibited by caloric restriction (De Lorenzo et al., 2011). In a molecular point of view, caloric restriction was recently shown to reverse inflammation in mammary glands of obese mice (Bhardwaj et al., 2013). A 30% caloric restriction was associated with more than 75% reduction of mammary histological inflammation, accompanied by decreased MCP-1 levels and normalization of levels of inflammatory mediators. Moreover, elevated aromatase level observed in obese mice was reversed following the caloric restriction and progesterone receptor expression, an estrogen-dependent gene, was subsequently decreased, suggesting that caloric restriction may reverse obesity-induced dysregulated AICAR synthesis signaling (Bhardwaj et al., 2013). Weight loss appears to have significant favorable effects on serum estrogen concentrations. A reduction of more than 20% of free estradiol is observed in postmenopausal women after a reduced-calorie weight loss diet. This reduction is even more pronounced if diet is accompanied with a physical activity (Campbell et al., 2012). Importantly, it should be noted that a very recent study reported that weight cycling, defined by weight loss and subsequent regain, is associated with negative health outcomes in postmenopausal women, including with higher risk of developing breast cancer (Welti et al., 2017). Numerous clinical studies have highlighted the superiority of aromatase inhibitors compared to antiestrogen therapies such as tamoxifen for hormone-dependent breast cancer treatment in postmenopausal women (Cuzick et al, 2010, Regan et al, 2011). However, these non-specific aromatase inhibitors induce a global estrogen deprivation throughout the body and are associated with several side effects. Indeed, estrogens have beneficial actions at many sites including bones and AICAR synthesis joint pains are the most commonly reported reason for discontinuing aromatase inhibitor used (Kemp et al., 2014). Targeting and inhibiting the aromatase promoter I.3/PII region in adipose stromal cells is an attractive therapeutic strategy to selectively block estrogen production at the tumor site. In the context of obesity and breast cancer, PGE2 is the key factor stimulating promoters I.3/PII via the activation of PKA and PKC pathways, as described above. These pathways may potentially be targeted, including by blocking PGE2 biosynthesis via the inhibition of COX-2 or by using PGE2 receptor antagonists (Bowers and deGraffenried, 2015).
    Conclusion It is now established that being overweight or obese elevates the risk of developing breast cancer, worsens prognosis and decreases survival in postmenopausal women. Obesity is a complex and multifaceted condition that remains incompletely understood as suggested by several data that remain controversial. However, the molecular mechanisms underlying the relationship between obesity and breast carcinogenesis are becoming increasingly clear. One of the main mechanisms through which obesity increases breast cancer risk is by considerably affecting estrogen signaling in the breast of postmenopausal women. Secreted obesity-related factors alter estrogen signaling in the breast of obese women in several ways; by inducing aromatase transcription in adipose stromal cells via a switch of promoter use, which is likely to be the main mechanism occurring in obese postmenopausal women, but also by enhancing aromatase activity, increasing local estrogen bioavailability or by regulating ER expression and activation. Dysregulated estrogen signaling, in turn, exhibits enhanced genomic and non-genomic actions creating local conditions favorable to breast carcinogenesis and tumor growth (Fig. 3). Therapeutic strategies aimed at reducing weight, adipose tissue inflammation or estrogen production may be efficacious at breaking this obesity-breast cancer relationship in postmenopausal women.