Effect of progesterone receptor A predominance on breast cancer cell migration into bone marrow fibroblasts
Effect of progesterone receptor A predominance on breast cancer cell migration into bone marrow fibroblasts
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DOI：
10.1023/b:brea.0000014041.58977.80
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发表时间：
2004-02-01
影响因子：
3.8
通讯作者：
Clarke, CL
中科院分区：
文献类型：
--
作者：
McGowan, EM;Saad, S;Clarke, CL
暴露于外源性孕酮的妇女患乳腺癌的风险增加，但孕酮参与乳腺癌发展的机制尚不清楚。在人类乳房和子宫内膜中，孕激素受体（PR）异构体表达在癌前病变中被破坏，在侵袭性癌症中，一种异构体（通常是PRA）的优势与较差的预后相关。PR异构体表达的中断导致黄体酮对细胞形态的调节中断，包括圆形形态和细胞对组织培养瓶的粘附性降低。本研究的目的是验证PRA优势影响乳腺癌细胞与生理相关基质组织骨髓基质相互作用的假设。T-47D乳腺癌细胞显示出向骨髓成纤维细胞迁移的能力，这种能力被黄体酮治疗抑制。抗黄体酮RU38486消除了黄体酮对迁移的影响，表明它是pr介导的。在表达PRA优势的细胞中，诱导稳定整合的可诱导PRA构建体后，黄体酮抑制乳腺癌细胞迁移的能力丧失。许多整合素在T-47D细胞中受到黄体酮的调节，但在PRA优势细胞中黄体酮的作用没有差异，这些细胞中局灶黏附蛋白的水平也没有改变。这表明，在PRA优势的细胞中，黄体酮对乳腺癌细胞迁移缺乏抑制并非由PRA对粘附连接膜组分的影响介导。综上所述，本研究表明，PRA优势对乳腺癌细胞向间质层迁移具有显著的功能作用。PRA优势可能使乳腺癌细胞相对抵抗黄体酮的抑制作用，其后果之一可能是增加基质的侵袭。如果在体内得到证实，这些发现表明，具有PRA优势的肿瘤可能倾向于癌症进展，这可能预示着患者预后较差。
Women exposed to exogenous progesterone have increased breast cancer risk, but the mechanisms of progesterone involvement in breast cancer development are unknown. In human breast and endometrium, progesterone receptor (PR) isoform expression is disrupted in premalignant lesions and predominance of one isoform, usually PRA, in invasive cancers is associated with poorer prognosis. Disrupted PR isoform expression results in disrupted progestin regulation of cell morphology, including rounded morphology and decreased adherence of cells to tissue culture flasks. The purpose of this study was to test the hypothesis that predominance of PRA affects the interaction of breast cancer cells with a physiologically relevant stromal tissue, bone marrow stroma. T-47D breast cancer cells demonstrated the ability to migrate into bone marrow fibroblasts and this was inhibited by progestin treatment. The antiprogestin RU38486 abrogated the progestin effect on migration, demonstrating that it was PR-mediated. In cells expressing a predominance of PRA, after induction of a stably integrated inducible PRA construct, the ability of progestin to inhibit breast cancer cell migration was lost. A number of integrins were progestin regulated in T-47D cells, but there was no difference in the progestin effect in cells with PRA predominance, nor were the levels of focal adhesion proteins altered in these cells. This suggested that the lack of inhibition by progestin of breast cancer cell migration in cells with PRA predominance was not mediated by PRA effects on the membrane components of the adherens junctions. In summary, this study has shown that PRA predominance has a striking functional effect on breast cancer cell migration into stromal layers. PRA predominance may render breast cancer cells relatively resistant to the inhibitory effects of progestins and one consequence of this may be increased invasion of stroma. If borne out in vivo, these findings suggest that tumours with PRA predominance may be predisposed to cancer progression and this may signal a poorer prognosis in patients.