Italian Institute for Genomic Medicine (IIGM), Candiolo, Turin, Italy.
Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin, Italy.
Cancer Res. 2021 Feb 1;81(3):535-536. doi: 10.1158/0008-5472.CAN-20-3903.
The study by Zagorac and colleagues represents an important step forward in the field of breast cancer, explaining a novel molecular mechanism of transition from slowly multiplying tumor-initiating cells (TIC) into their more differentiated version characterized by high proliferation. The mechanism involves the transcription factors SOX2 and EZH2, which directly repress transcription of cell-cycle genes and activate self-renewal genes in breast cancer cells. This mechanism is further controlled by a negative feedback loop mediated by a long noncoding RNA, , not described previously, which is upregulated in tumorspheres and inhibits SOX2 and EZH2. is an atypical tumor suppressor in breast cancer, being upregulated in cancer cells, but counteracting their aggressive phenotype. At the molecular level, by direct interaction with EZH2, inhibits the transcriptional activity of EZH2 and "blocks the shot" of cancer cells' self-renewal. From a translational perspective, activating or induction of SCIRT mimetics in breast cancer cells may lead to the dedifferentiation of TICs toward a less protumorigenic phenotype and a therapy-fragile state that could open new therapeutic avenues..
Zagorac 及其同事的研究代表了乳腺癌领域的重要进展，解释了肿瘤起始细胞（TIC）从缓慢增殖到高增殖的更分化状态的新型分子机制。该机制涉及转录因子 SOX2 和 EZH2，它们直接抑制细胞周期基因的转录，并激活乳腺癌细胞中的自我更新基因。该机制进一步受到长非编码 RNA 介导的负反馈回路的控制，该 RNA 以前未被描述，在肿瘤球体中上调，并抑制 SOX2 和 EZH2。 在乳腺癌中是一种非典型的肿瘤抑制因子，在癌细胞中上调，但抵消了它们的侵袭表型。在分子水平上， 通过与 EZH2 的直接相互作用， 抑制了 EZH2 的转录活性，并“阻止了癌细胞自我更新的枪击”。从转化的角度来看，激活 或诱导乳腺癌细胞中的 SCIRT 类似物可能导致 TIC 向肿瘤发生能力较低的表型和治疗脆弱状态的去分化，从而开辟新的治疗途径。
