PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis
PAPAS promotes differentiation of mammary epithelial cells and suppresses breast carcinogenesis
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DOI：
10.1016/j.celrep.2023.113644
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发表时间：
2024-01-04
期刊：
影响因子：
8.8
通讯作者：
Bierhoff，Holger
中科院分区：
文献类型：
--
作者：
Ren，Sijia;Bai，Feng;Bierhoff，Holger
女性乳腺上皮在发育和妊娠期间的广泛重塑与癌症易感性有关。乳腺上皮细胞（MEC）对激素信号的忠实反应是避免乳腺癌发展的关键。在这里，我们表明，催乳分化的小鼠MEC需要沉默的基因编码核糖体RNA（rRNA）的反义transcriptPAPAS。因此，敲低PAPAS可使rRNA基因去抑制，减弱对催乳激素的反应，并诱导恶性转化。恢复乳腺癌细胞中的PAPAS水平可降低致瘤性和肺侵袭，并激活许多以前与转移抑制相关的干扰素调节基因。PAPAS的转录机制依赖于rRNA基因3′端的R环形成，而在乳腺癌细胞中，RNA酶H1和复制蛋白A（RPA）的过表达抑制了R-loop的形成。人乳腺癌中PAPAS的缺失和RNase H1和RPA的上调支持了我们研究结果的临床意义。
Extensive remodeling of the female mammary epithelium during development and pregnancy has been linked to cancer susceptibility. The faithful response of mammary epithelial cells (MECs) to hormone signaling is key to avoiding breast cancer development. Here, we show that lactogenic differentiation of murine MECs requires silencing of genes encoding ribosomal RNA (rRNA) by the antisense transcriptPAPAS. Accordingly, knockdown ofPAPASderepresses rRNA genes, attenuates the response to lactogenic hormones, and induces malignant transformation. RestoringPAPASlevels in breast cancer cells reduces tumorigenicity and lung invasion and activates many interferon-regulated genes previously linked to metastasis suppression. Mechanistically,PAPAStranscription depends on R-loop formation at the 3′ end of rRNA genes, which is repressed by RNase H1 and replication protein A (RPA) overexpression in breast cancer cells. Depletion ofPAPASand upregulation of RNase H1 and RPA in human breast cancer underpin the clinical relevance of our findings.