INSERM-UMR1033, Lyon, France.
University of Lyon1, Lyon, France.
Oncogene. 2019 Feb;38(7):950-964. doi: 10.1038/s41388-018-0579-3. Epub 2018 Nov 26.
Bone is the most common metastatic site for breast cancer. Estrogen-related-receptor alpha (ERRα) has been implicated in cancer cell invasiveness. Here, we established that ERRα promotes spontaneous metastatic dissemination of breast cancer cells from primary mammary tumors to the skeleton. We carried out cohort studies, pharmacological inhibition, gain-of-function analyses in vivo and cellular and molecular studies in vitro to identify new biomarkers in breast cancer metastases. Meta-analysis of human primary breast tumors revealed that high ERRα expression levels were associated with bone but not lung metastases. ERRα expression was also detected in circulating tumor cells from metastatic breast cancer patients. ERRα overexpression in murine 4T1 breast cancer cells promoted spontaneous bone micro-metastases formation when tumor cells were inoculated orthotopically, whereas lung metastases occurred irrespective of ERRα expression level. In vivo, Rank was identified as a target for ERRα. That was confirmed in vitro in Rankl stimulated tumor cell invasion, in mTOR/pS6K phosphorylation, by transactivation assay, ChIP and bioinformatics analyses. Moreover, pharmacological inhibition of ERRα reduced primary tumor growth, bone micro-metastases formation and Rank expression in vitro and in vivo. Transcriptomic studies and meta-analysis confirmed a positive association between metastases and ERRα/RANK in breast cancer patients and also revealed a positive correlation between ERRα and BRCA1 carriers. Taken together, our results reveal a novel ERRα/RANK axis by which ERRα in primary breast cancer promotes early dissemination of cancer cells to bone. These findings suggest that ERRα may be a useful therapeutic target to prevent bone metastases.
骨骼是乳腺癌最常见的转移部位。雌激素相关受体-α（ERRα）已被牵连到癌细胞的侵袭性中。在这里，我们确定 ERRα 促进了乳腺癌细胞从原发性乳腺肿瘤自发转移扩散到骨骼。我们进行了队列研究、药理学抑制、体内增益功能分析以及体外细胞和分子研究，以确定乳腺癌转移的新生物标志物。对人类原发性乳腺癌的荟萃分析显示，高 ERRα 表达水平与骨转移而非肺转移有关。转移性乳腺癌患者的循环肿瘤细胞中也检测到 ERRα 表达。当肿瘤细胞原位接种时，ERRα 在鼠 4T1 乳腺癌细胞中的过表达促进了自发骨微转移的形成，而肺转移的发生与 ERRα 表达水平无关。在体内，Rank 被鉴定为 ERRα 的靶标。这在 Rankl 刺激的肿瘤细胞侵袭、mTOR/pS6K 磷酸化、转激活测定、ChIP 和生物信息学分析中通过体外实验得到了证实。此外，ERRα 的药理学抑制减少了体内外原发性肿瘤生长、骨微转移形成和 Rank 表达。转录组学研究和荟萃分析证实了 ERRα/RANK 在乳腺癌患者中的转移之间存在正相关，并且还显示了 ERRα 与 BRCA1 携带者之间的正相关。总之，我们的研究结果揭示了一个新的 ERRα/RANK 轴，通过该轴，原发性乳腺癌中的 ERRα 促进了癌细胞向骨骼的早期扩散。这些发现表明，ERRα 可能是预防骨转移的有用治疗靶点。
