Lester and Sue Smith Breast Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Dan L. Duncan Cancer Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
Program in Quantitative and Computational Biosciences, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA; Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, TX 77030, USA.
Dev Cell. 2021 Apr 19;56(8):1100-1117.e9. doi: 10.1016/j.devcel.2021.03.008.
Estrogen receptor-positive (ER) breast cancer exhibits a strong bone tropism in metastasis. How the bone microenvironment (BME) impacts ER signaling and endocrine therapy remains poorly understood. Here, we discover that the osteogenic niche transiently and reversibly reduces ER expression and activities specifically in bone micrometastases (BMMs), leading to endocrine resistance. As BMMs progress, the ER reduction and endocrine resistance may partially recover in cancer cells away from the osteogenic niche, creating phenotypic heterogeneity in macrometastases. Using multiple approaches, including an evolving barcoding strategy, we demonstrated that this process is independent of clonal selection, and represents an EZH2-mediated epigenomic reprogramming. EZH2 drives ER BMMs toward a basal and stem-like state. EZH2 inhibition reverses endocrine resistance. These data exemplify how epigenomic adaptation to BME promotes phenotypic plasticity of metastatic seeds, fosters intra-metastatic heterogeneity, and alters therapeutic responses. Our study provides insights into the clinical enigma of ER+ metastatic recurrences despite endocrine therapies.
雌激素受体阳性（ER）乳腺癌在转移中表现出强烈的骨骼趋向性。骨微环境（BME）如何影响 ER 信号和内分泌治疗仍知之甚少。在这里，我们发现成骨龛在骨微转移（BMM）中特异性地短暂和可逆地降低 ER 表达和活性，导致内分泌抵抗。随着 BMM 的进展，远离成骨龛的癌细胞中 ER 减少和内分泌抵抗可能部分恢复，在大转移灶中产生表型异质性。通过多种方法，包括不断发展的条形码策略，我们证明了这个过程独立于克隆选择，代表了 EZH2 介导的表观基因组重编程。EZH2 将 ER BMM 推向基底和干细胞样状态。EZH2 抑制逆转内分泌抵抗。这些数据说明了 BME 中的表观基因组适应如何促进转移性种子的表型可塑性，促进肿瘤内异质性，并改变治疗反应。我们的研究为尽管进行了内分泌治疗但仍出现 ER+转移性复发的临床难题提供了一些见解。
