Department of Molecular Diagnostics and Cancer Cell Biology, Genentech, Inc., South San Francisco, CA, USA.
Sci Signal. 2011 Aug 9;4(186):pt5. doi: 10.1126/scisignal.2002258.
Compared with the luminal subtype, the basal-like subtype of breast cancer has an aggressive clinical behavior, but the reasons for this difference between the two subtypes are poorly understood. We identified microRNAs (miRNAs) miR-221 and miR-222 (miR-221/222) as basal-like subtype-specific miRNAs that decrease expression of epithelial-specific genes and increase expression of mesenchymal-specific genes. In addition, expression of these miRNAs increased cell migration and invasion, which collectively are characteristics of the epithelial-to-mesenchymal transition (EMT). The basal-like transcription factor FOSL1 (also known as Fra-1) directly stimulated the transcription of miR-221/222, and the abundance of these miRNAs decreased with inhibition of MEK (mitogen-activated or extracellular signal-regulated protein kinase kinase), placing miR-221/222 downstream of the RAS pathway. The miR-221/222-mediated reduction in E-cadherin abundance depended on their targeting of the 3' untranslated region (3'UTR) of TRPS1 (trichorhinophalangeal syndrome type 1), which is a member of the GATA family of transcriptional repressors. TRPS1 inhibited EMT by directly repressing expression of ZEB2 (Zinc finger E-box-binding homeobox 2). Therefore, miR-221/222 may contribute to the aggressive clinical behavior of basal-like breast cancers.
与腔面型相比，乳腺癌的基底样亚型具有侵袭性的临床行为，但这两种亚型之间的差异的原因尚不清楚。我们确定了 microRNAs (miRNAs) miR-221 和 miR-222（miR-221/222）为基底样亚型特异性 miRNAs，其降低上皮特异性基因的表达并增加间充质特异性基因的表达。此外，这些 miRNAs 的表达增加了细胞迁移和侵袭，这共同是上皮间质转化（EMT）的特征。基底样转录因子 FOSL1（也称为 Fra-1）直接刺激 miR-221/222 的转录，并且这些 miRNAs 的丰度随着 MEK（丝裂原激活或细胞外信号调节蛋白激酶激酶）的抑制而降低，将 miR-221/222 置于 RAS 通路的下游。miR-221/222 介导的 E-钙粘蛋白丰度降低取决于它们对 TRPS1（三联体综合征 1 型）的 3'非翻译区（3'UTR）的靶向，TRPS1 是转录阻遏物 GATA 家族的成员。TRPS1 通过直接抑制 ZEB2（锌指 E-盒结合同源盒 2）的表达来抑制 EMT。因此，miR-221/222 可能有助于基底样乳腺癌的侵袭性临床行为。
