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首页> 外文期刊>Molecular Cancer >Global profiling of prolactin-modulated transcripts in breast cancer in vivo
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Global profiling of prolactin-modulated transcripts in breast cancer in vivo

机译：体内乳腺癌中催乳素调节的转录本的全球概况

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Background Prolactin (PRL) is essential for normal mammary gland development. PRL promotes mammary tumor formation in rodents and elevated serum prolactin is associated with increased risk of estrogen-receptor positive breast cancer in women. On the other hand, PRL may also exert pro-differentiation effects and act to suppress invasive features of established breast cancer. Previously published limited global transcript profiling analyses of prolactin-regulated gene expression in human breast cancer cells have exclusively been performed in vitro . The present study aimed to shed new light on how PRL modulates estrogen receptor (ER)-positive breast cancer through global transcript profiling of a human breast cancer xenograft model in vivo . Methods The prolactin-responsive human T47D breast cancer cell line was xenotransplanted into nude mice and global transcript profiling was carried out following treatment with or without human PRL for 48?h. A subset of PRL-modulated transcripts was further validated using qRT-PCR and immunohistochemistry. Results The in vivo analyses identified 130 PRL-modulated transcripts, 75 upregulated and 55 downregulated, based on fold change >1.6 and P-value in vitro . The selected PRL-modulated transcripts were tested for dependence on Stat5, Jak1 or Jak2 activation, and for co-regulation by 17β-estradiol (E2). The protein encoded by one of the PRL-regulated transcripts, PTHrP , was examined in a panel of 92 human breast cancers and found by in situ quantitative immunofluorescence analysis to be highly positively correlated with nuclear localized and tyrosine phosphorylated Stat5. Gene Ontology analysis revealed that PRL-upregulated genes were enriched in pathways involved in differentiation. Finally, a gene signature based on PRL-upregulated genes was associated with prolonged relapse-free and metastasis-free survival in breast cancer patients. Conclusions This global analysis identified and validated a panel of PRL-modulated transcripts in an ER-positive human breast cancer xenotransplant model, which may have value as markers of relapse-free and metastasis-free survival. Gene products identified in the present study may facilitate ongoing deciphering of the pleiotropic effects of PRL on human breast cancer.
机译：背景催乳素（PRL）对于正常的乳腺发育至关重要。 PRL促进啮齿动物的乳腺肿瘤形成，血清催乳素升高与女性雌激素受体阳性乳腺癌的风险增加有关。另一方面，PRL还可能发挥促分化作用，并抑制已建立的乳腺癌的浸润性。以前发表的有关人类乳腺癌细胞中催乳素调节基因表达的有限全球转录谱分析仅在体外进行。本研究旨在通过体内人类乳腺癌异种移植模型的整体转录谱分析，揭示PRL如何调节雌激素受体（ER）阳性乳腺癌。方法将催乳素反应性人T47D乳腺癌细胞系异种移植到裸鼠中，并在有或没有人PRL处理48？h后进行整体转录谱分析。使用qRT-PCR和免疫组织化学进一步验证了PRL调节的转录物的子集。结果体内分析基于> 1.6倍变化和体外P值，鉴定出130种PRL调节的转录本，上调75种，下调55种。测试了所选PRL调节的转录本对Stat5，Jak1或Jak2激活的依赖性，以及对17β-雌二醇（E2）的共调节作用。由PRL调控的转录物之一PTHrP编码的蛋白质在92例人类乳腺癌中进行了检测，并通过原位定量免疫荧光分析发现与核定位和酪氨酸磷酸化Stat5高度正相关。基因本体分析显示PRL上调的基因丰富了参与分化的途径。最后，基于PRL上调基因的基因签名与乳腺癌患者延长的无复发和无转移生存期相关。结论这项全球分析确定并验证了ER阳性人类乳腺癌异种移植模型中一组PRL调节的转录本，这些转录本可能具有无复发和无转移生存的标志物的价值。在本研究中确定的基因产物可能有助于不断解密PRL对人类乳腺癌的多效性作用。

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