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  • Macrophages in bone metastasis main outstanding questions br


    Macrophages in bone metastasis – main outstanding questions:
    Conflict of interest statement
    Acknowledgements IV was supported by a generous grant from Weston Park Hospital Cancer Charity, Sheffield, UK.
    Introduction In recent years there has been increasing interest in the role of bone-targeted agents, such as bisphosphonates (BP) and denosumab, as adjuvant therapies for breast cancer. The results of large randomized trials with BPs have been variable showing either; benefit [1–3], no benefit [4–7] or harm [8]. However, subgroup analyses have consistently shown that, where benefit exists, it is in women with a “low PalMitoyl Tripeptide-1 manufacturer environment” either through menopause or suppression of ovarian function. In this manuscript, we review the link between estrogen and breast cancer risk and the hypothesis that estrogen levels may in part explain the response of patients to bone-targeted agents in the adjuvant setting.
    Estrogen and breast cancer link The pivotal role of cyclical estrogens in breast cancer risk is well recognized. This has been shown in epidemiological studies where risk is related to earlier age at menarche, later age at first birth and menopause, and parity [9,10]. Breastfeeding is protective and is theorized to be secondary to increased prolactin secretion and subsequent suppression of estrogen production [11–13]. Studies on hormone replacement therapy (HRT) have shown increased risk of breast cancer while receiving combined estrogen and progesterone hormone replacement [14,15] and, interestingly, a fall in risk on discontinuation [15–17]. Obesity has also been shown to increase breast cancer risk in postmenopausal women, which is likely due to adipose tissue facilitating the conversion of adrenally secreted dehydroepiandrosterone (DHEA) into estrogen, leading to elevated estrogen levels [18]. In addition, several studies note that higher serum levels of estrogen in postmenopausal women are associated with increased breast cancer risk [19–23]. A meta-analysis of nine prospective studies, with data on 2428 predominantly postmenopausal women, 663 with breast cancer, demonstrated a roughly twofold higher risk of breast cancer in women with higher serum estrogen (2nd–4th quartiles) compared to those with lower levels (1st quartile) [24].
    Estrogen and bone The importance of estrogen is maintaining bone health is well recognized [25,26]. The bone microenvironment is dynamic with on-going remodeling through the activity of both osteoclasts (bone resorption) and osteoblasts (bone formation). Osteoclastogenesis is tightly regulated by the receptor activator of nuclear factor kappa B ligand (RANKL), receptor activator of nuclear factor kappa B (RANK) and osteoprotegerin (OPG) system. RANKL is a protein synthesized by preosteoblast cells. When these proteins bind to their receptors (RANK) on osteoclast precursor cells, they stimulate osteoclast differentiation and activation, resulting in bone resorption [27,28]. Preosteoblast cells also express OPG, a soluble decoy receptor that binds to RANKL and blocks the interaction between RANKL and its receptor RANK, thereby inhibiting osteoclastogenesis [29,30]. OPG is also known to induce apoptosis in mature osteoclasts, further limiting bone resorption [31]. The amount of bone resorption is dependent on the balance between RANKL and OPG. Many cytokines and hormones are involved in regulation of the RANKL/RANK/OPG system, including sex steroids [27,30]. Estrogen is known to inhibit RANKL production [27,30], and stimulate the production of OPG [32,33]. Thus, estrogen deficient states result in increased RANKL production, which in turn overwhelms the OPG decoy receptors. This results in greater osteoclastogenesis and excessive bone resorption, which may eventually lead to reduced bone density. Throughout this process, growth factors are released into the bone microenvironment, which is hypothesized to result in tumor cell proliferation and survival [34,35]. Thus, in estrogen deficient states, increased release of growth factors driven by increased osteoclastic resorption activity may provide a favorable environment for tumor growth and progression. As such, bone-targeted therapies such as BPs that inhibit osteoclast activation, should in theory limit growth factor release and hence tumor cell proliferation.