Ligand-dependent activation of transcription by nuclear receptors (NRs) is mediated by interactions with coactivators. Receptor agonists promote coactivator binding, and antagonists block coactivator binding. Here we report the crystal structure of the human estrogen receptor alpha (hER alpha) ligand-binding domain (LBD) bound to both the agonist diethylstilbestrol (DES) and a peptide derived from the NR box II region of the coactivator GRIP1 and the crystal structure of the hER alpha LBD bound to the selective antagonist 4-hydroxytamoxifen (OHT). In the DES-LBD-peptide complex, the peptide binds as a short alpha helix to a hydrophobic groove on the surface of the LBD. In the OHT-LBD complex, helix 12 occludes the coactivator recognition groove by mimicking the interactions of the NR box peptide with the LBD. These structures reveal the two distinct mechanisms by which structural features of OHT promote this "autoinhibitory" helix 12 conformation.

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In recent years, neutrophils have attracted increasing attention because of their cancer-promoting effects. An elevated neutrophil-to-lymphocyte ratio is considered a prognostic indicator for patients with cancer. Neutrophils are no longer regarded as innate immune cells with a single function, let alone bystanders in the pathological process of cancer. Their diversity and plasticity are being increasingly recognized. This review summarizes previous studies assessing the roles and mechanisms of neutrophils in cancer initiation, progression, metastasis and relapse. Although the findings are controversial, the fact that neutrophils play a dual role in promoting and suppressing cancer is undeniable. The plasticity of neutrophils allows them to adapt to different cancer microenvironments and exert different effects on cancer. Given the findings from our own research, we propose a reasonable hypothesis that neutrophils may be reprogrammed into a cancer-promoting state in the cancer microenvironment. This new perspective indicates that neutrophil reprogramming in the course of cancer treatment is a problem worthy of attention. Preventing or reversing the reprogramming of neutrophils may be a potential strategy for adjuvant cancer therapy.