Department of Comparative Biosciences, University of Wisconsin, Madison, Wisconsin 53706, USA.
J Biol Chem. 2013 May 3;288(18):12722-32. doi: 10.1074/jbc.M112.447631. Epub 2013 Mar 24.
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.
临床上，循环催乳素水平和细胞外基质 (ECM) 的密度是乳腺癌的个体风险因素。随着肿瘤的发展，周围基质会对胶原蛋白基质的增加沉积和交联（纤维化）做出反应。在小鼠模型中，催乳素促进类似于女性中腔乳腺癌的乳腺肿瘤，并且胶原蛋白密度的增加促进肿瘤转移和进展。尽管 ECM 对催乳素生理作用的贡献越来越被理解，但 ECM 与乳腺癌中催乳素信号之间的功能关系知之甚少。在这里，我们研究了细胞外基质硬度增加对体外三维 I 型胶原蛋白基质中腔乳腺癌细胞催乳素信号的影响。我们表明，基质硬度有力地调节了催乳素信号从生理到促肿瘤结局的转变。顺应性基质促进了生理催乳素作用和 STAT5 的激活，而刚性基质促进了促肿瘤结局，包括增加基质金属蛋白酶依赖性侵袭和胶原蛋白支架重新排列。在刚性基质中，催乳素增加了 SRC 家族激酶依赖性酪氨酸 925 处粘着斑激酶 (FAK) 的磷酸化、FAK 与丝裂原活化蛋白激酶介质 GRB2 的关联以及 pERK1/2。刚性基质还增加了催乳素受体和整合素激活的 FAK 的共定位，暗示了空间关系的改变。总之，这些结果表明，细胞外基质硬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以正反馈回路相互作用。我们的研究首次报道了乳腺癌中细胞外基质-催乳素相互作用的改变，这表明可能有新的治疗方法。
