PDF(Pubmed)
Abstract：
Breast cancer bone metastases (BMET) are incurable, primarily osteolytic, and occur most commonly in estrogen receptor-α positive (ER+) breast cancer. ER+ human breast cancer BMET modeling in mice has demonstrated an estrogen (E2)-dependent increase in tumor-associated osteolysis and bone-resorbing osteoclasts, independent of estrogenic effects on tumor proliferation or bone turnover, suggesting a possible mechanistic link between tumoral ERα-driven osteolysis and ER+ bone progression. To explore this question, inducible secretion of the osteolytic factor, parathyroid hormone-related protein (PTHrP), was utilized as an in vitro screening bioassay to query the osteolytic potential of estrogen receptor- and signaling pathway-specific ligands in BMET-forming ER+ human breast cancer cells expressing ERα, ERß, and G protein-coupled ER. After identifying genomic ERα signaling, also responsibility for estrogen\'s proliferative effects, as necessary and sufficient for osteolytic PTHrP secretion, in vivo effects of a genomic-only ER agonist, estetrol (E4), on osteolytic ER+ BMET progression were examined. Surprisingly, while pharmacologic effects of E4 on estrogen-dependent tissues, including bone, were evident, E4 did not support osteolytic BMET progression (vs robust E2 effects), suggesting an important role for nongenomic ER signaling in ER+ metastatic progression at this site. Because bone effects of E4 did not completely recapitulate those of E2, the relative importance of nongenomic ER signaling in tumor vs bone cannot be ascertained here. Nonetheless, these intriguing findings suggest that targeted manipulation of estrogen signaling to mitigate ER+ metastatic progression in bone may require a nuanced approach, considering genomic and nongenomic effects of ER signaling on both sides of the tumor/bone interface.
摘要：
乳腺癌骨转移（BMET）是无法治愈的，主要是溶骨，最常见于雌激素受体-α阳性（ER+）乳腺癌。ER+人乳腺癌小鼠BMET模型已证明肿瘤相关骨溶解和骨吸收破骨细胞的雌激素（E2）依赖性增加，不依赖于雌激素对肿瘤增殖或骨转换的影响，提示肿瘤ERα驱动的骨溶解与ER+骨进展之间可能的机制联系。为了探索这个问题，溶骨因子的可诱导分泌，甲状旁腺激素相关蛋白（PTHrP），被用作体外筛选生物测定法，以查询表达ERα的BMET形成ER的人乳腺癌细胞中雌激素受体和信号通路特异性配体的溶骨潜力，ERβ,和G蛋白偶联的ER。在鉴定基因组ERα信号后，也负责雌激素的增殖作用，对于溶骨性PTHrP分泌来说是必要和充分的，仅基因组ER激动剂的体内作用，雌四醇（E4），对溶骨性ER+BMET进展进行了检查。令人惊讶的是,而E4对雌激素依赖性组织的药理作用，包括骨头,很明显,E4不支持溶骨性BMET进展（与强E2效应相比），提示非基因组ER信号在该部位的ER+转移进展中的重要作用。因为E4的骨作用不能完全概括E2的骨作用,所以这里不能确定非基因组ER信号在肿瘤和骨中的相对重要性。尽管如此，这些有趣的发现表明，雌激素信号的靶向操作，以减轻ER+骨转移进展可能需要一个微妙的方法，考虑ER信号在肿瘤/骨界面两侧的基因组和非基因组效应。
