Breast cancer ranks no. 1 in women cancer worldwide, while 60–70% are estrogen receptor alpha positive. The estrogen selective modulators, such as tamoxifen, become the effective drugs for controlling ER alpha breast cancer progression. However, tamoxifen resistance will develop during long-time treatment and cancer progression. Thus, further understanding of ER alpha signaling becomes necessary for the improvement of breast cancer therapy. Here, we identify TRIM56 as a novel regulatory factor in ER alpha signaling. TRIM56 expression is positively correlated with ER alpha and PR in breast cancer samples and is related to poor prognosis in endocrine therapy patients. TRIM56 depletion significantly decreases ER alpha signaling activity and ER-alpha-positive breast cancer proliferation in vitro and in vivo. TRIM56 associates with AF1 domain of ER alpha via its WD40 domain in the cytoplasm. TRIM56 prolongs ER alpha protein stability, possibly through targeting ER alpha K63-linked ubiquitination. In conclusion, our study reveals an interesting posttranslational mechanism between TRIM56 and ER alpha in breast cancer progression. Targeting TRIM56 could be a promising approach for ER-alpha-positive breast cancer.

乳腺癌排名第一。在全世界女性癌症中占1位，而60-70％的雌激素受体α阳性。雌激素选择性调节剂，如他莫昔芬，成为控制ERα乳腺癌进展的有效药物。但是，在长期治疗和癌症进展期间会产生他莫昔芬耐药性。因此，对ERα信号的进一步理解对于改善乳腺癌治疗变得必要。在这里，我们将TRIM56识别为ER alpha信号传导中的新型调节因子。TRIM56表达与乳腺癌样品中的ER alpha和PR正相关，并且与内分泌治疗患者的不良预后有关。TRIM56耗竭显着降低了体内外的ERα信号传导活性和ERαα阳性乳腺癌的增殖。TRIM56通过其在细胞质中的WD40结构域与ER alpha的AF1结构域相关联。TRIM56可能通过靶向ER alpha K63连接的泛素化来延长ER alpha蛋白的稳定性。总而言之，我们的研究揭示了TRIM56和ER alpha之间在乳腺癌进展中有趣的翻译后机制。靶向TRIM56可能是ER-α阳性乳腺癌的有前途的方法。