Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage.
Matrix density-induced mechanoregulation of breast cell phenotype, signaling and gene expression through a FAK-ERK linkage.
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DOI：
10.1038/onc.2009.299
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发表时间：
2009-12-10
期刊：
影响因子：
8
通讯作者：
Keely, P. J.
中科院分区：
文献类型：
--
作者：
Provenzano, P. P.;Inman, D. R.;Eliceiri, K. W.;Keely, P. J.
关键词：
乳房 X 光检查致密的乳腺组织是发生乳腺癌的最大危险因素之一，但相关的分子机制仍然很大程度上未知。重要的是，乳腺密度高的区域与基质胶原和上皮细胞含量增加有关。我们着手确定在没有基质细胞的情况下增加的胶原基质密度是否足以促进非转化乳腺上皮细胞中恶性表型的增殖和侵袭特征。我们证明，增加的胶原基质密度会增加基质硬度，从而促进侵袭表型。高基质硬度导致激活的 3D 基质粘连的形成增加，以及由外向内/由内向外的 FAK-Rho 信号环路长期升高，这是产生和维持侵入表型所必需的。此外，该信号网络导致 Ras-MAPK 通路过度激活，从而促进乳腺上皮细胞在体外和体内的生长，并激活可预测患者结果的临床相关增殖特征。因此，目前的数据为微环境机械特征的重要性提供了令人信服的证据，并表明这些细胞中的机械转导是通过 FAK-Rho-ERK 信号网络发生的，其中 ERK 作为瓶颈，通过该瓶颈调节对机械刺激的大部分反应。因此，我们提出，基质硬度的增加解释了乳腺组织密度高的人类患者上皮增殖和癌症风险增加背后的部分机制。
Mammographically dense breast tissue is one of the greatest risk factors for developing breast carcinoma, yet the associated molecular mechanisms remain largely unknown. Importantly, regions of high breast density are associated with increased stromal collagen and epithelial cell content. We set out to determine if increased collagen matrix density, in the absence of stromal cells, was sufficient to promote proliferation and invasion characteristic of a malignant phenotype in non-transformed mammary epithelial cells. We demonstrate that increased collagen matrix density increases matrix stiffness to promote an invasive phenotype. High matrix stiffness resulted in the increased formation of activated 3D-matrix adhesions and a chronically elevated outside-in/inside-out FAK-Rho signaling loop, which was necessary to generate and maintain the invasive phenotype. Moreover, this signaling network resulted in hyperactivation of the Ras-MAPK pathway, which promoted growth of mammary epithelial cells in vitro and in vivo and activated a clinically relevant proliferation signature that predicts patient outcome. Hence, the current data provides compelling evidence for the importance of the mechanical features of the microenvironment and suggest that mechanotransduction in these cells occurs through a FAK-Rho-ERK signaling network with ERK as a bottleneck through which much of the response to mechanical stimuli is regulated. As such, we propose that increased matrix stiffness explains part of the mechanism behind increased epithelial proliferation and cancer risk in human patients with high breast tissue density.
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影响因子：
64.5
作者：
Choquet, D;Felsenfeld, DP;Sheetz, MP
通讯作者：
Sheetz, MP
影响因子：
4.7
作者：
Boyd, N F;Martin, L J;Yaffe, M J
通讯作者：
Yaffe, M J
影响因子：
3.5
作者：
Plewes, DB;Bishop, J;Sciarretta, J
通讯作者：
Sciarretta, J
DOI：
10.1083/jcb.200204153
发表时间：
2002-11-25
期刊：
The Journal of cell biology
影响因子：
--
作者：
Galbraith CG;Yamada KM;Sheetz MP
通讯作者：
Sheetz MP
影响因子：
3.8
作者：
Li, T;Sun, LM;Boyd, N
通讯作者：
Boyd, N