Effect of conditional knockout of the type II TGF-β receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis
Effect of conditional knockout of the type II TGF-β receptor gene in mammary epithelia on mammary gland development and polyomavirus middle T antigen induced tumor formation and metastasis
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DOI：
10.1158/0008-5472.can-04-3272
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发表时间：
2005-03-15
期刊：
影响因子：
11.2
通讯作者：
Moses, HL
中科院分区：
文献类型：
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作者：
Forrester, E;Chytil, A;Moses, HL
转化生长因子-β（TGF-β）同种型是在生理上起作用以调节发育、细胞增殖和免疫应答的生长因子。TGF-β信号传导在乳腺肿瘤发生中的作用是复杂的，因为已报道TGF-β既作为肿瘤抑制剂又作为肿瘤促进剂起作用。为了阐明TGF-β信号传导在乳腺发育、肿瘤发生和转移中的作用，将编码II型TGF-β受体Tgfbr 2的基因在乳腺上皮中条件性缺失（Tgfbr 2（MGKO））。乳腺上皮中Tgfbr 2的缺失导致发育中的乳腺小叶-肺泡增生和细胞凋亡增加。将Tgfbr 2（MGKO）小鼠与转移性乳腺癌的小鼠乳腺肿瘤病毒-多核糖核酸病毒中T抗原（PyVmT）转基因小鼠模型交配。在PyVmT表达的背景下Tgfbr 2的缺失导致中位肿瘤潜伏期缩短和肺转移形成增加。因此，我们的研究支持上皮TGF-β信号传导在乳腺肿瘤发生中的肿瘤抑制作用，并表明在癌细胞中TGF-β信号传导不存在的情况下，肺转移可以发生甚至增强。
Transforming growth factor-beta (TGF-beta) isoforms are growth factors that function physiologically to regulate development, cellular proliferation, and immune responses. The role of TGF-beta signaling in mammary tumorigenesis is complex, as TGF-beta has been reported to function as both a tumor suppressor and tumor promoter. To elucidate the role of TGF-beta signaling in mammary gland development, tumorigenesis, and metastasis, the gene encoding type II TGF-beta receptor, Tgfbr2, was conditionally deleted in the mammary epithelium (Tgfbr2(MGKO)). Loss of Tgfbr2 in the mammary epithelium results in lobular-alveolar hyperplasia in the developing mammary gland and increased apoptosis. Tgfbr2(MGKO) mice were mated to the mouse mammary tumor virus-polyornavirus middle T antigen (PyVmT) transgenic mouse model of metastatic breast cancer. Loss of Tgfbr2 in the context of PyVmT expression results in a shortened median tumor latency and an increased formation of pulmonary metastases. Thus, our studies support a tumor-suppressive role for epithelial TGF-beta signaling in mammary gland turnorigenesis and show that pulmonary metastases can occur and are even enhanced in the absence of TGF-beta signaling in the carcinoma cells.