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  • br Among the subpopulations of immature myeloid cells that


    Among the subpopulations of immature myeloid Erteberel that fre-quently arise during tumor progression and metastasis, myeloid-derived suppressor cells (MDSC) are known to express ER, and estrogen sig-naling is reported to promote MDSC expansion and activation in pre-clinical studies [7]. MDSC are also identified in the TME of BC biopsies from the clinic [16,17] and consist of two large groups of immune cells termed granulocytic or polymorphonuclear cells (G-MDSC), which are phenotypically and morphologically similar to neutrophils, and mono-cytic cells (M-MDSC) similar to monocytes. Immune suppression is a major property of MDSC, with T-cells the main targets of MDSC action [16,17] Accordingly, estrogen antagonists may disrupt BC progression by diminishing MDSC numbers and associated pro-tumorigenic func-tions potentially regardless of the ER status of the tumor. Among the challenges to make immuno-therapy a more effective intervention in BC management going forward, it is important to find ways to manipulate additional mechanisms of tumor immune tolerance and to enhance T-effector cell infiltration and access to the tumor. It is therefore rea-sonable to investigate the concept that BC escape from immune attack may be blocked by potent antiestrogens that exert antitumor activity in certain ER-positive immune cells, actions that should boost the action of ICI.
    It is well established that estrogens modulate BC gene transcription by binding ER with high affinity, thereby activating downstream sig-naling by use of genomic pathways that involve direct DNA binding of ligand-bound ER to estrogen-responsive elements in the promoter re-gions of responsive genes. In addition, nongenomic pathways often involve indirect modulation of transcription by ER interactions with components of other transcription or growth factor receptor kinase signaling complexes (such as MAPK, PI3K/AKT) via specific protein-protein interactions [18]. Current reports indicate that estrogen sig-naling in MDSC occurs in part by the induced phosphorylation and activation of STAT3 which stimulates downstream signaling for the expansion of MDSC [7]. STAT3 is required for MDSC survival and proliferation and also modulates expression of S100A8 and S100A9 proteins that are important for regulating MDSC expansion and mi-gration to tumor sites [7,8].
    Antiestrogen therapy with tamoxifen has been widely used for more than 40 years, with evidence from clinical trials for significant 
    reductions in BC mortality in ER-positive early BC [1,19]. Although effective, tamoxifen has important drawbacks, including a limited period of activity before drug resistance; and an increased risk of en-dometrial cancer and thromboemboli due to its partial agonist activity as a selective ER modulator [2,3,20]. Use of AIs for postmenopausal patients has yielded better outcomes than the standard of 5 years ta-moxifen [2,19,21]; but in patients with advanced breast cancer, only about 1/3 of ER-positive BCs respond to AIs, and resistance can evolve due to ER activation by different mechanisms such as ligand-in-dependent activation [2,3,20–22] or emergence of ESR1 mutations [23,24]. Consequently, a search is underway to discover new anti-estrogens that lack agonist activity and override endocrine-resistance [20,25]. As long as ER is present in breast tumors, growth may be sti-mulated by estrogen, partial agonists or estrogen-independent action. The first selective ER downregulator (SERD), fulvestrant, has no major agonist activity and good antitumor efficacy [20,26,27]. However, fulvestrant has very low bioavailability that is a significant liability in clinic [28]. Although fulvestrant has activity in ER-positive BCs that progress after AIs or tamoxifen including some patients with ESR1 mutations, discovery of improved SERDs with improved bioavailability and antitumor activity is a key goal. In 14–20% of metastatic ER-po-sitive BCs from patients with multiple prior endocrine therapies, there is evidence for acquisition of functionally-aberrant ESR1 with point mutations often occurring in the ER ligand-binding domain, most commonly at D538 G and Y537S [23,24]. Some mutant ESR1 variants may continue to respond to fulvestrant, but higher doses of fulvestrant are required to achieve wild-type levels of tumor inhibition. Current data show that achievement of higher optimal doses of fulvestrant by intramuscular drug delivery is not feasible and underscore the need to develop more potent SERDs with enhanced bioavailability in advanced BC. A Erteberel number of non-steroidal SERD candidates have been assessed, with many failing to advance beyond Phase I-II trials due to agonist activity in normal tissues, other off-target adverse side-effects or for unknown reasons [29,30]. With this history, we elected to design es-tradiol-like SERDs targeting ER that differ from proposed nonsteroidal drugs. These new SERDs and fulvestrant were then assessed for anti-tumor activity in BCs as well as in ER-positive immune cells that occupy the TME and interactions with immune checkpoint inhibitors that may be beneficial to management of both ER-positive and potentially ER-negative BCs in the clinic.