Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells
Stiff Collagen Matrices Increase Tumorigenic Prolactin Signaling in Breast Cancer Cells
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DOI：
10.1074/jbc.m112.447631
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发表时间：
2013-05-03
影响因子：
4.8
通讯作者：
Schuler, Linda A.
中科院分区：
文献类型：
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作者：
Barcus, Craig E.;Keely, Patricia J.;Schuler, Linda A.
临床上，循环催乳素水平和细胞外基质（ECM）密度是乳腺癌的个体风险因素。随着肿瘤的发展，周围的间质以增加的胶原基质沉积和交联（结缔组织增生）作出反应。在小鼠模型中，催乳素促进类似于女性管腔乳腺癌的乳腺癌，胶原蛋白密度增加促进肿瘤转移和进展。虽然越来越多地了解ECM的催乳素的生理作用的贡献，很少有人知道ECM和催乳素信号之间的功能关系在乳腺癌。在这里，我们研究的后果增加ECM刚度催乳素信号的管腔乳腺癌细胞在三维胶原蛋白I矩阵在体外。我们发现，基质硬度有力地调节开关催乳素信号从生理促肿瘤的结果。顺应性基质促进生理催乳素作用和STAT 5的活化，而刚性基质促进促肿瘤发生结果，包括增加基质金属蛋白酶依赖性侵袭和胶原支架重新排列。在硬基质中，催乳素增加SRC家族激酶依赖的粘着斑激酶（FAK）酪氨酸925磷酸化，FAK与促分裂原活化蛋白激酶介体GRB 2和pERK 1/2的结合。僵硬的基质也增加了催乳素受体和整合素激活的FAK的共定位，这意味着空间关系的改变。总之，这些结果表明，ECM刚度是催乳素信号谱的强大调节剂，并且刚性基质和催乳素在乳腺癌进展中的前馈回路中相互作用。我们的研究是第一个报告的证据，改变ECM催乳素相互作用在乳腺癌，这表明新的治疗方法的潜力。
Clinically, circulating prolactin levels and density of the extracellular matrix (ECM) are individual risk factors for breast cancer. As tumors develop, the surrounding stroma responds with increased deposition and cross-linking of the collagen matrix (desmoplasia). In mouse models, prolactin promotes mammary carcinomas that resemble luminal breast cancers in women, and increased collagen density promotes tumor metastasis and progression. Although the contributions of the ECM to the physiologic actions of prolactin are increasingly understood, little is known about the functional relationship between the ECM and prolactin signaling in breast cancer. Here, we examined consequences of increased ECM stiffness on prolactin signals to luminal breast cancer cells in three-dimensional collagen I matrices in vitro. We showed that matrix stiffness potently regulates a switch in prolactin signals from physiologic to protumorigenic outcomes. Compliant matrices promoted physiological prolactin actions and activation of STAT5, whereas stiff matrices promoted protumorigenic outcomes, including increased matrix metalloproteinase-dependent invasion and collagen scaffold realignment. In stiff matrices, prolactin increased SRC family kinase-dependent phosphorylation of focal adhesion kinase (FAK) at tyrosine 925, FAK association with the mitogen-activated protein kinase mediator GRB2, and pERK1/2. Stiff matrices also increased co-localization of prolactin receptors and integrin-activated FAK, implicating altered spatial relationships. Together, these results demonstrate that ECM stiffness is a powerful regulator of the spectrum of prolactin signals and that stiff matrices and prolactin interact in a feed-forward loop in breast cancer progression. Our study is the first reported evidence of altered ECM-prolactin interactions in breast cancer, suggesting the potential for new therapeutic approaches.