TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model.
TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model.
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DOI：
10.1186/1471-213x-11-65
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发表时间：
2011-10-31
影响因子：
--
通讯作者：
Huang T
中科院分区：
文献类型：
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作者：
Liu J;Esmailpour T;Shang X;Gulsen G;Liu A;Huang T
T-box转录因子TBX 3是早期胚胎发育和乳腺正常发育所必需的。在小鼠中，纯合突变是胚胎致死的，而杂合突变导致乳腺发育紊乱。在人类中，导致TBX 3单倍不足的突变会导致以乳腺发育不全以及其他先天性缺陷为特征的尺骨乳腺综合征（UMS）。除了在乳腺发育中的作用外，各种研究还支持Tbx 3在乳腺癌发展中的作用。TBX 3在各种乳腺癌细胞系以及癌组织中过表达，并且已发现有助于乳腺癌细胞迁移。先前的研究表明，TBX 3通过抑制p14 ARF肿瘤抑制因子的表达而绕过衰老的能力，从而促进癌症的发展。尽管许多研究表明TBX 3表达失调可能有助于癌症进展，但没有直接证据表明TBX 3导致乳腺癌。在这项研究中，我们创建了多西环素诱导的双转基因小鼠（MMTV-rtTA;tet-myc-TBX 3-IRES-荧光素酶），以测试TBX 3过表达是否可以诱导乳腺内的肿瘤形成。虽然TBX 3单独过表达不会诱导肿瘤形成，但它确实通过增加乳腺上皮细胞增殖促进乳腺发育加速。我们还发现TBX 3直接结合并抑制NFκ B B，这是一种已知在调节细胞增殖中起作用的NF-κB通路抑制剂。最后，我们还表明TBX 3的过表达与乳腺干细胞样细胞的增加有关。总之，我们的数据表明，TBX 3的过度表达可能通过抑制NF-κB通路和刺激乳腺上皮细胞和干细胞样细胞增殖促进乳腺发育加速而促进乳腺癌的发展。
The T-box transcription factor TBX3 is necessary for early embryonic development and for the normal development of the mammary gland. Homozygous mutations, in mice, are embryonic lethal while heterozygous mutations result in perturbed mammary gland development. In humans, mutations that result in the haploinsufficiency of TBX3 causes Ulnar Mammary Syndrome (UMS) characterized by mammary gland hypoplasia as well as other congenital defects. In addition to its role in mammary gland development, various studies have also supported a role for Tbx3 in breast cancer development. TBX3 is over-expressed in various breast cancer cell lines as well as cancer tissue and has been found to contribute to breast cancer cell migration. Previous studies have suggested that TBX3 contributes to cancer development by its ability to bypass senescence by repressing the expression of p14ARF-tumor suppressor. Although many studies have shown that a dysregulation of TBX3 expression may contribute to cancer progression, no direct evidence shows TBX3 causes breast cancer. In this study, we created doxycycline inducible double transgenic mice (MMTV-rtTA;tet-myc-TBX3-IRES-Luciferase) to test whether TBX3 over-expression can induce tumor formation within the mammary gland. Although over-expression of TBX3, alone, did not induce tumor formation it did promote accelerated mammary gland development by increasing mammary epithelial cell proliferation. We also show that TBX3 directly binds to and represses NFκBIB, an inhibitor of the NF-κB pathway known to play a role in regulating cell proliferation. Lastly, we also show that the over-expression of TBX3 is associated with an increase in mammary stem-like cells. Overall, our data suggests that over-expression of TBX3 may contribute to breast cancer development by promoting accelerated mammary gland development through the inhibition of the NF-κB pathway and stimulation of both mammary epithelial cell and stem-like cell proliferation.