Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways
Progestin effects on breast cancer cell proliferation, proteases activation, and in vivo development of metastatic phenotype all depend on progesterone receptor capacity to activate cytoplasmic signaling pathways
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DOI：
10.1210/me.2006-0304
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发表时间：
2007-06-01
影响因子：
--
通讯作者：
Elizalde, Patricia V.
中科院分区：
文献类型：
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作者：
Carnevale, Romina P.;Proietti, Cecilia J.;Elizalde, Patricia V.
越来越多的证据表明，孕激素参与控制乳腺肿瘤的发生。在这里，我们评估了不同表型乳腺癌模型中孕激素作用的分子机制。我们检测了C4HD细胞，孕激素发挥持续增殖反应的雌激素(ER)和孕酮(PR)受体阳性的小鼠乳腺癌模型，缺乏PR和ER表达的LM3小鼠转移性乳腺癌细胞株，以及人PR缺失的T47D-Y乳腺癌细胞。PR除了作为转录因子外，还可以作为信号通路的激活剂。为了探索这两个功能中的哪一个与孕激素反应有关，我们用野生型PR-B、DNA结合突变体C587A-PR和缺乏激活细胞质信号通路能力的突变体PR-BmPro在PR阴性模型中进行了重构实验。我们发现，在ER阳性或阴性的细胞环境中，孕激素通过MAPK和磷脂酰肌醇3-激酶/Akt通路诱导表达野生型PR-B或DNA结合突变体C587A-PR的细胞生长和调节基质金属蛋白酶-9(MMP9)和基质金属蛋白酶-2(MMP2)以及尿激酶型纤溶酶原激活物(UPA)的活性。相反，在表达突变PR-BmPro的细胞中，孕激素不能诱导生长。我们还发现，与缺乏PR表达的细胞相比，去连接PR表达使乳腺癌细胞在体外具有较低的增殖表型。当PR作为转录因子或信号激活剂发挥作用时，这种行为就会发生调节。最后，我们首次证明了孕激素通过PR作为信号通路的激活剂来促进乳腺肿瘤转移的发展。我们目前的发现为设计一种新的治疗PR阳性乳腺肿瘤的干预措施提供了机制支持，该干预措施包括阻断PR激活细胞质信号的能力。
Accumulating evidence indicates that progestins are involved in controlling mammary gland tumorigenesis. Here, we assessed the molecular mechanisms of progestin action in breast cancer models with different phenotypes. We examined C4HD cells, an estrogen (ER) and progesterone (PR) receptor-positive murine breast cancer model in which progestins exert sustained proliferative response, the LM3 murine metastatic mammary tumor cell line, which lacks PR and ER expression, and human PR null T47D-Y breast cancer cells. In addition to acting as a transcription factor, PR can also function as an activator of signaling pathways. To explore which of these two functions were involved in progestin responses, reconstitution experiments in the PR-negative models were performed with wild-type PR-B, with a DNA binding mutant C587A-PR, and with mutant PR-BmPro, which lacks the ability to activate cytoplasm signaling pathways. We found that in a cell context either ER-positive or -negative, progestins induced cell growth and modulation of matrix metalloproteinases-9 (MMP-9) and -2 (MMP-2), and urokinase-type plasminogen activator (uPA) activities, via MAPK and phosphatidylinositol 3-kinase/Akt pathways, in cells expressing wildtype PR-B or DNA binding mutant C587A-PR. In contrast, in cells expressing mutant PR-BmPro, progestins did not induce growth. We also found that unliganded PR expression conferred breast cancer cells an in vitro less proliferative phenotype, as compared with cells lacking PR expression. Modulation of this behavior occurred when PR was functioning either as transcription factor or as signaling activator. Finally, we for the first time demonstrated that progestins favor development of breast tumor metastasis via PR function as activator of signaling pathways. Our present findings provide mechanistic support to the design of a novel therapeutic intervention in PR-positive breast tumors involving blockage of PR capacity to activate cytoplasmic signaling.