p130Cas over-expression impairs mammary branching morphogenesis in response to estrogen and EGF.
p130Cas over-expression impairs mammary branching morphogenesis in response to estrogen and EGF.
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DOI：
10.1371/journal.pone.0049817
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Cabodi S
中科院分区：
文献类型：
--
作者：
Camacho Leal Mdel P;Pincini A;Tornillo G;Fiorito E;Bisaro B;Di Luca E;Turco E;Defilippi P;Cabodi S
P130Cas接头蛋白调控细胞周期调控、存活和迁移等基本过程。P130Cas过表达与乳腺转化有关，但p130Cas过表达在乳腺形态发生过程中的体内后果尚不清楚。在MMTV-p130Cas转基因小鼠的体外乳腺组织中，我们发现p130Cas在乳腺发育过程中削弱了表皮生长因子受体(EGFR)和雌激素受体(ER)之间的功能相互作用。事实上，我们证明，在EGF和雌激素(E2)的共同刺激下，p130Cas的过度表达严重损害了乳腺的形态发生，导致结构改变和中央管腔缺失的增大的多细胞球形结构。这些充满的腺泡结构的特征是细胞存活和增殖增加，ERK1/2 MAPKs和Akt被强烈激活。有趣的是，拮抗ER活性足以重建分支形态发生和正常的ERK1/2 MAPK活性。总体而言，这些结果表明，高水平的p130Cas表达通过改变上皮结构、生存和平衡ERK1/2 MAPKs的激活来深刻地影响乳腺形态发生。这些结果提示，p130Cas过度表达引起的形态发生通路的改变可能是乳腺上皮细胞发生肿瘤的基础。
p130Cas adaptor protein regulates basic processes such as cell cycle control, survival and migration. p130Cas over-expression has been related to mammary gland transformation, however the in vivo consequences of p130Cas over-expression during mammary gland morphogenesis are not known. In ex vivo mammary explants from MMTV-p130Cas transgenic mice, we show that p130Cas impairs the functional interplay between Epidermal Growth Factor Receptor (EGFR) and Estrogen Receptor (ER) during mammary gland development. Indeed, we demonstrate that p130Cas over-expression upon the concomitant stimulation with EGF and estrogen (E2) severely impairs mammary morphogenesis giving rise to enlarged multicellular spherical structures with altered architecture and absence of the central lumen. These filled acinar structures are characterized by increased cell survival and proliferation and by a strong activation of Erk1/2 MAPKs and Akt. Interestingly, antagonizing the ER activity is sufficient to re-establish branching morphogenesis and normal Erk1/2 MAPK activity. Overall, these results indicate that high levels of p130Cas expression profoundly affect mammary morphogenesis by altering epithelial architecture, survival and unbalancing Erk1/2 MAPKs activation in response to growth factors and hormones. These results suggest that alteration of morphogenetic pathways due to p130Cas over-expression might prime mammary epithelium to tumorigenesis.
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影响因子：
4.8
作者：
Cabodi, Sara;Tinnirello, Agata;Defilippi, Paola
通讯作者：
Defilippi, Paola
影响因子：
8
作者：
Cowell, L. N.;D Graham, J.;O'Neill, G. M.
通讯作者：
O'Neill, G. M.
影响因子：
2.7
作者：
Auricchio, Ferdinando;Migliaccio, Antimo;Castoria, Gabriella
通讯作者：
Castoria, Gabriella
影响因子：
2.5
作者：
Fagan, Dedra H.;Yee, Douglas
通讯作者：
Yee, Douglas
DOI：
10.1016/j.bbrc.2005.08.256
发表时间：
2005-11-04
影响因子：
3.1
作者：
Lee, YR;Park, J;Jung, SH
通讯作者：
Jung, SH