Oncology Program, Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
CIBERONC, Madrid, Spain.
Nat Cell Biol. 2018 Feb;20(2):211-221. doi: 10.1038/s41556-017-0021-z. Epub 2018 Jan 22.
For many patients with breast cancer, symptomatic bone metastases appear after years of latency. How micrometastatic lesions remain dormant and undetectable before initiating colonization is unclear. Here, we describe a mechanism involved in bone metastatic latency of oestrogen receptor-positive (ER) breast cancer. Using an in vivo genome-wide short hairpin RNA screening, we identified the kinase MSK1 as an important regulator of metastatic dormancy in breast cancer. In patients with ER breast cancer, low MSK1 expression associates with early metastasis. We show that MSK1 downregulation impairs the differentiation of breast cancer cells, increasing their bone homing and growth capacities. MSK1 controls the expression of genes required for luminal cell differentiation, including the GATA3 and FOXA1 transcription factors, by modulating their promoter chromatin status. Our results indicate that MSK1 prevents metastatic progression of ER breast cancer, suggesting that stratifying patients with breast cancer as high or low risk for early relapse based on MSK1 expression could improve prognosis.
对于许多患有乳腺癌的患者来说，有症状的骨转移在潜伏期多年后才出现。在开始定植之前，微转移病灶如何保持休眠和不可检测尚不清楚。在这里，我们描述了一种涉及雌激素受体阳性（ER）乳腺癌骨转移潜伏期的机制。使用体内全基因组短发夹 RNA 筛选，我们鉴定出激酶 MSK1 是乳腺癌转移休眠的重要调节因子。在 ER 乳腺癌患者中，MSK1 低表达与早期转移相关。我们表明，MSK1 的下调会损害乳腺癌细胞的分化，增加其归巢和生长能力。MSK1 通过调节其启动子染色质状态来控制包括 GATA3 和 FOXA1 转录因子在内的管腔细胞分化所需基因的表达。我们的结果表明，MSK1 可防止 ER 乳腺癌的转移进展，这表明基于 MSK1 表达将乳腺癌患者分层为高风险或低风险以早期复发可能会改善预后。
