It is now well established that

It is now well established that the cumulative exposure to endogenous estrogens throughout a woman's life, mainly due to her reproductive history, has an impact on the risk of hormone-dependent breast cancer (Lambertini et al., 2016). Prolonged exposure to estrogens in the case of early age at menarche or late menopause can, for example, increase the risk of breast cancer (Collaborative Group on Hormonal Factors in Breast, 1996). Several epidemiological and clinical studies have confirmed this correlation between hormones and breast malignancy by reporting higher serum levels of estrogens in women with breast cancer compared to control cases (Thomas et al., 1997, Dorgan et al, 1996, Toniolo et al, 1995). ER is predominantly a nuclear protein that functions as a ligand-dependent transcription factor. Mechanistically, in the classical way, after dimerization and co-regulator recruitment, the E2/ER complexes can directly bind estrogen response elements in the promoter region of target genes (Gerard et al., 2015). This process leads to the regulation of transcription of estrogen-responsive genes that are important in various physiological and pathological processes, including carcinogenesis and tumor progression (Welboren et al., 2009). Besides these classical genomic effects, E2 can also elicit extra-nuclear or non-genomic actions related to the activation of rapid signaling pathways (Kampa et al., 2008). These extra-nuclear effects are mediated via a pool of ER present at the membrane or in the Levodopa receptor and lead to the rapid activation of downstream targets such as the mitogen-activated protein kinases (MAPK) pathway, which in turn modifies various cellular functions (Raffo et al., 2015). Another putative estrogen membrane receptor termed G protein-coupled estrogen receptor 1 (GPER), also known as G protein-coupled receptor 30 (GPR30), has been more recently proposed to contribute to physiological and tumor promoting effects of estrogens (Prossnitz and Barton, 2011, Maggiolini et al, 2004). Both the genomic and non-genomic actions of E2 play pivotal roles and are necessary for the E2-induced proliferation and survival of cancer cells (Acconcia and Marino, 2003). The most common and effective adjuvant therapy against ER-positive breast cancers is based on estrogen suppression and/or blocking the interaction with its receptor, an approach generally called endocrine therapy (Early Breast Cancer Trialists' Collaborative G et al, 2011, Cuzick et al, 2010). Tamoxifen, a selective estrogen receptor modulator, was the drug of choice for more than 30 years to treat patients with hormone-dependent breast tumors. The use of tamoxifen has considerably improved survival of early-stage breast cancer patients and reduced recurrence rates (Effects of chemotherapy a, 2005). Over time, aromatase inhibitors have proven more effective, mainly because of their improved side effect profile. They are now first line therapy for postmenopausal women (Cuzick et al, 2010, Regan et al, 2011). While association of obesity with different breast cancer subtypes is not fully understood and conflictual data have been reported by some authors, a growing body of evidence strongly suggests that the association between obesity and postmenopausal breast cancer is the highest among hormone receptor-positive cases (Suzuki et al, 2009, Canchola et al, 2012, Rosenberg et al, 2006). A meta-analysis including 5469 cases and comparing the highest versus the reference categories of relative body weight, revealed that the risk of hormone receptor-positive tumors was 82% higher among postmenopausal women and showed that each 5-unit increase in BMI was associated with a 33% increased risk (Suzuki et al., 2009). Importantly, obesity has also been associated with an increased risk of ER-negative breast cancers, suggesting that there are likely to be several hormone-independent mechanisms also involved in the link between obesity and breast cancer development (Daling et al, 2001, Gershuni et al, 2017). These observations might also highlight a potential role of the ER present in tumor microenvironment or the implication of other receptors, such as GPER, in mediating the effects of E2 in these tumors (Pequeux et al, 2012, Pupo et al., 2016).