Rap1 integrates tissue polarity, lumen formation, and tumorigenic potential in human breast epithelial cells
Rap1 integrates tissue polarity, lumen formation, and tumorigenic potential in human breast epithelial cells
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DOI：
10.1158/0008-5472.can-06-4246
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发表时间：
2007-05-15
期刊：
影响因子：
11.2
通讯作者：
Bissell, Mina J.
中科院分区：
文献类型：
--
作者：
Itoh, Masahiko;Nelson, Celeste M.;Bissell, Mina J.
正常乳腺腺泡上皮的顶基底极性维持需要细胞增殖、细胞死亡和适当的细胞-细胞和细胞-细胞外基质信号传导之间的平衡。这些过程中的任何异常都可能破坏组织结构并引发肿瘤的形成。在这里，我们发现小的GTPase Rap1是组织腺泡结构和诱导管腔形成的关键因素。恶性HMT-3522 T4-2细胞中Rap1活性明显高于非恶性细胞S1细胞。显性阴性Rap1的表达导致T4-2细胞表型逆转，形成极性正确的腺泡结构，尽管基因组异常和基线生长持续存在，但仍显著降低肿瘤发生率。当使用其他恢复剂时，所产生的腺泡含有突出的中央腔。相反，在T4-2细胞中，显性活性Rap1的表达抑制表型逆转，导致侵袭性和致瘤性增加。因此，Rap1作为乳腺结构的中枢调节因子，在腺泡形态发生过程中，正常水平的激活指示极性，而增加的激活诱导肿瘤形成和恶性进展。
Maintenance of apico-basal polarity in normal breast epithelial acini requires a balance between cell proliferation, cell death, and proper cell-cell and cell-extracellular matrix signaling. Aberrations in any of these processes can disrupt tissue architecture and initiate tumor formation. Here, we show that the small GTPase Rap1 is a crucial element in organizing acinar structure and inducing lumen formation. Rap1 activity in malignant HMT-3522 T4-2 cells is appreciably higher than in S1 cells, their nonmalignant counterparts. Expression of dominant-negative Rap1 resulted in phenotypic reversion of T4-2 cells, led to the formation of acinar structures with correct polarity, and dramatically reduced tumor incidence despite the persistence of genomic abnormalities and baseline growth. The resulting acini contained prominent central lumina not observed when other reverting agents were used. Conversely, expression of dominant-active Rap1 in T4-2 cells inhibited phenotypic reversion and led to increased invasiveness and tumorigenicity. Thus, Rap1 acts as a central regulator of breast architecture, with normal levels of activation instructing polarity during acinar morphogenesis, and increased activation inducing tumor formation and progression to malignancy.