Kim Hyung Bum, Kraus W Lee
Laboratory of Signaling and Gene Regulation, Cecil H. and Ida Green Center for Reproductive Biology Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
Section of Laboratory Research, Department of Obstetrics and Gynecology, University of Texas Southwestern Medical Center, Dallas, Texas.
Mol Cancer Res. 2025 Apr 1;23(4):313-326. doi: 10.1158/1541-7786.MCR-24-0533.
Elevated blood levels of estrogens have been associated with poor prognosis in estrogen receptor-positive (ER+) breast cancers, but the relationship between circulating hormone levels in the blood and intracellular hormone concentrations is not well characterized. We observed that MCF-7 cells treated acutely with 17β-estradiol (E2) retain a substantial amount of the hormone even upon the removal of the hormone from the culture medium. Moreover, global patterns of E2-dependent gene expression are sustained for hours after acute E2 treatment and hormone removal. Although circulating E2 is sequestered by sex hormone binding globulin, the potential mechanisms of intracellular E2 retention are poorly understood. We found that mislocalization of a steroid-binding GRAM domain-containing protein, ASTER-B, to the nucleus, which is observed in a subset of patients with breast cancer, is associated with higher cellular E2 retention. Accumulation and retention of E2 are related to the steroidal properties of E2 and require nuclear localization and steroid binding by ASTER-B, as shown using a panel of mutant ASTER-B proteins. Finally, we observed that nuclear ASTER-B-mediated E2 retention is required for sustained hormone-induced ERα chromatin occupancy at enhancers and gene expression, as well as subsequent cell growth responses. Our results add intracellular hormone retention as a mechanism controlling E2-dependent gene expression and downstream biological outcomes. Implications: Mislocalized nuclear ASTER-B, which binds estradiol to support the functions of ER, can provide an alternate means of enhancing the biological effects of E2 in breast cancers and may be a potential therapeutic target that addresses multiple aspects of estrogen bioavailability.
雌激素水平升高与雌激素受体阳性（ER+）乳腺癌的不良预后相关，但血液中循环激素水平与细胞内激素浓度之间的关系尚未得到充分表征。我们观察到，用17β-雌二醇（E2）急性处理的MCF-7细胞即使在从培养基中去除激素后仍保留大量该激素。此外，急性E2处理和激素去除后，E2依赖性基因表达的整体模式会持续数小时。尽管循环中的E2会被性激素结合球蛋白隔离，但细胞内E2保留的潜在机制仍知之甚少。我们发现，在一部分乳腺癌患者中观察到的一种含类固醇结合GRAM结构域的蛋白ASTER-B向细胞核的错误定位与更高的细胞E2保留有关。E2的积累和保留与E2的类固醇特性有关，并且需要ASTER-B的核定位和类固醇结合，如使用一组突变型ASTER-B蛋白所显示的那样。最后，我们观察到核ASTER-B介导的E2保留是激素诱导的ERα在增强子处的染色质占据和基因表达以及随后的细胞生长反应持续所必需的。我们的结果增加了细胞内激素保留作为控制E2依赖性基因表达和下游生物学结果的一种机制。意义：错误定位的核ASTER-B与雌二醇结合以支持ER的功能，可以提供一种增强E2在乳腺癌中生物学效应的替代方法，并且可能是一个解决雌激素生物利用度多个方面的潜在治疗靶点。
