Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells.
Dense collagen-I matrices enhance pro-tumorigenic estrogen-prolactin crosstalk in MCF-7 and T47D breast cancer cells.
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DOI：
10.1371/journal.pone.0116891
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Schuler LA
中科院分区：
文献类型：
--
作者：
Barcus CE;Holt EC;Keely PJ;Eliceiri KW;Schuler LA
表达雌激素受体α(ERα+)的乳腺癌占乳腺肿瘤的大多数。雌激素是它们生长的主要驱动力，靶向ER介导的信号是一种很大程度上成功的主要治疗策略。尽管如此，ERα+肿瘤也导致了最多的乳腺癌死亡率。其他因素，包括细胞外基质特性的改变，如密度和取向，以及雌激素与催乳素(PRL)等其他激素的串扰后果，可能是导致这些不良结果的原因。在此，我们采用已定义的三维低密度/顺应性和高密度/刚性胶原-I基质，在体外研究了17β-雌二醇(E_2)活性和PRL/E_2相互作用对两个具有良好特性的ER_α+/PRL_2+腔内乳腺癌细胞系的影响。我们证明，基质密度调节E2诱导的转录本，但不改变生长反应。然而，基质密度是PRL/E2串扰行为结果的一个强有力的决定因素。高密度/刚性基质增强了PRL/E2诱导的生长，其机制是通过增加Src家族的激活和对雌激素拮抗剂4-羟基三苯氧胺的不敏感而实现的。它还允许这些激素组合来驱动侵袭和改变胶原纤维的排列。相反，低密度/顺应性基质允许E2和PRL之间适度的合作以促进生长，而不允许激素诱导的侵袭或胶原蛋白重定位。我们的研究证明了基质密度决定激素作用结果的能力，并提示刚性基质是雌激素和催乳素在ERα+乳腺癌进展中的有力协作者。我们关于这些激素和细胞外基质之间双向相互作用的证据为调控ERα+乳腺癌的微环境提供了新的见解，并提出了新的治疗方法。
Breast cancers that express estrogen receptor alpha (ERα+) constitute the majority of breast tumors. Estrogen is a major driver of their growth, and targeting ER-mediated signals is a largely successful primary therapeutic strategy. Nonetheless, ERα+ tumors also result in the most breast cancer mortalities. Other factors, including altered characteristics of the extracellular matrix such as density and orientation and consequences for estrogen crosstalk with other hormones such as prolactin (PRL), may contribute to these poor outcomes. Here we employed defined three dimensional low density/compliant and high density/stiff collagen-I matrices to investigate the effects on 17β-estradiol (E2) activity and PRL/E2 interactions in two well-characterized ERα+/PRLR+ luminal breast cancer cell lines in vitro. We demonstrate that matrix density modulated E2-induced transcripts, but did not alter the growth response. However, matrix density was a potent determinant of the behavioral outcomes of PRL/E2 crosstalk. High density/stiff matrices enhanced PRL/E2-induced growth mediated by increased activation of Src family kinases and insensitivity to the estrogen antagonist, 4-hydroxytamoxifen. It also permitted these hormones in combination to drive invasion and modify the alignment of collagen fibers. In contrast, low density/compliant matrices allowed modest if any cooperation between E2 and PRL to growth and did not permit hormone-induced invasion or collagen reorientation. Our studies demonstrate the power of matrix density to determine the outcomes of hormone actions and suggest that stiff matrices are potent collaborators of estrogen and PRL in progression of ERα+ breast cancer. Our evidence for bidirectional interactions between these hormones and the extracellular matrix provides novel insights into the regulation of the microenvironment of ERα+ breast cancer and suggests new therapeutic approaches.
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影响因子：
10.3
作者：
Glass, Andrew G.;Lacey, James V., Jr.;Hoover, Robert N.
通讯作者：
Hoover, Robert N.
影响因子：
3.8
作者：
Chen, YenHao;Huang, KuangTzu;Walker, Ameae M.
通讯作者：
Walker, Ameae M.
影响因子：
11.2
作者：
Gilkes DM;Chaturvedi P;Bajpai S;Wong CC;Wei H;Pitcairn S;Hubbi ME;Wirtz D;Semenza GL
通讯作者：
Semenza GL
影响因子：
30.8
作者：
Carroll, Jason S.;Meyer, Clifford A.;Brown, Myles
通讯作者：
Brown, Myles
影响因子：
6
作者：
Arendt, Lisa M.;Grafwallner-Huseth, Tara L.;Schuler, Linda A.
通讯作者：
Schuler, Linda A.