Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression.
Haploinsufficiency for p190B RhoGAP inhibits MMTV-Neu tumor progression.
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DOI：
10.1186/bcr2352
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发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Rosen JM
中科院分区：
文献类型：
--
作者：
Heckman-Stoddard BM;Vargo-Gogola T;McHenry PR;Jiang V;Herrick MP;Hilsenbeck SG;Settleman J;Rosen JM
Rho 信号传导调节关键的细胞过程，包括增殖、存活和迁移，并且与包括乳腺癌在内的多种癌症的发生有关。 P190B Rho GTP 酶激活蛋白 (RhoGAP) 是 Rho GTP 酶的主要抑制剂。 P190B 是乳腺形态发生所必需的，p190B 在乳腺中的过度表达会诱发增生性病变。因此，我们假设p190B可能在乳腺肿瘤发生中发挥关键作用。为了研究 p190B 功能丧失对乳腺肿瘤进展的影响，将 p190B 杂合小鼠与 MMTV-Neu 乳腺癌模型杂交。评估了 p190B 缺陷对肿瘤潜伏期、多重性、生长、肿瘤前进展和转移的影响。为了研究两组之间肿瘤血管生成的潜在差异，进行了免疫组织化学检测冯维勒布兰德因子并进行定量。为了检查血管生成开关的潜在介质的基因表达，使用血管生成PCR阵列并使用免疫组织化学确认结果。最后，进行肿瘤碎片的相互移植以确定p190B基质缺陷对肿瘤血管生成的影响。 P190B 缺陷降低了肿瘤外显率（53% 的 p190B+/-Neu 小鼠形成肿瘤，而 100% 的 p190B+/+Neu 小鼠形成肿瘤），并显着延迟肿瘤发生，平均延迟 46 周。肿瘤多重性也降低，但检测到癌前病变数量增加，表明 p190B 缺陷抑制癌前进展。 p190B 杂合肿瘤中的血管生成减少，p190B+/-Neu 乳腺中有效的血管生成抑制剂血小板反应蛋白-1 的表达升高。将 p190B+/-Neu 肿瘤片段移植到野生型受体中可恢复肿瘤血管生成。引人注目的是，p190B+/+Neu 肿瘤片段在移植到 p190B+/-Neu 受体中时无法生长。这些数据表明上皮中的 p190B 单倍体不足抑制 MMTV-Neu 肿瘤的发生。此外，脉管系统中的 p190B 缺陷在一定程度上是抑制 MMTV-Neu 肿瘤进展的原因。
Rho signaling regulates key cellular processes including proliferation, survival, and migration, and it has been implicated in the development of many types of cancer including breast cancer. P190B Rho GTPase activating protein (RhoGAP) functions as a major inhibitor of the Rho GTPases. P190B is required for mammary gland morphogenesis, and overexpression of p190B in the mammary gland induces hyperplastic lesions. Hence, we hypothesized that p190B may play a pivotal role in mammary tumorigenesis. To investigate the effects of loss of p190B function on mammary tumor progression, p190B heterozygous mice were crossed with an MMTV-Neu breast cancer model. Effects of p190B deficiency on tumor latency, multiplicity, growth, preneoplastic progression and metastasis were evaluated. To investigate potential differences in tumor angiogenesis between the two groups, immunohistochemistry to detect von Willebrand factor was performed and quantified. To examine gene expression of potential mediators of the angiogenic switch, an angiogenesis PCR array was utilized and results were confirmed using immunohistochemistry. Finally, reciprocal transplantation of tumor fragments was performed to determine the impact of stromal deficiency of p190B on tumor angiogenesis. P190B deficiency reduced tumor penetrance (53% of p190B+/-Neu mice vs. 100% of p190B+/+Neu mice formed tumors) and markedly delayed tumor onset by an average of 46 weeks. Tumor multiplicity was also decreased, but an increase in the number of preneoplastic lesions was detected indicating that p190B deficiency inhibited preneoplastic progression. Angiogenesis was decreased in the p190B heterozygous tumors, and expression of a potent angiogenic inhibitor, thrombospondin-1, was elevated in p190B+/-Neu mammary glands. Transplantation of p190B+/-Neu tumor fragments into wild-type recipients restored tumor angiogenesis. Strikingly, p190B+/+Neu tumor fragments were unable to grow when transplanted into p190B+/-Neu recipients. These data suggest that p190B haploinsufficiency in the epithelium inhibits MMTV-Neu tumor initiation. Furthermore, p190B deficiency in the vasculature is responsible, in part, for the inhibition of MMTV-Neu tumor progression.
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DOI：
10.1073/pnas.171460498
发表时间：
2001-10-23
影响因子：
11.1
作者：
Rodríguez-Manzaneque, JC;Lane, TF;Iruela-Arispe, ML
通讯作者：
Iruela-Arispe, ML
影响因子：
2.7
作者：
Heckman, Brandy M.;Chakravarty, Geetika;Rosen, Jeffrey M.
通讯作者：
Rosen, Jeffrey M.
DOI：
10.1016/j.cub.2008.09.019
发表时间：
2008-10-28
期刊：
Current biology : CB
影响因子：
--
作者：
Bustos RI;Forget MA;Settleman JE;Hansen SH
通讯作者：
Hansen SH
影响因子：
4.3
作者：
Naumov, George N.;Akslen, Lars A.;Folkman, Judah
通讯作者：
Folkman, Judah
影响因子：
8
作者：
Schnelzer, A;Prechtel, D;Lengyel, E
通讯作者：
Lengyel, E