Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival.
Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival.
复制标题
DOI：
10.1186/bcr2448
复制
发表时间：
2009
期刊：
影响因子：
--
通讯作者：
Horseman ND
中科院分区：
文献类型：
--
作者：
Pai VP;Marshall AM;Hernandez LL;Buckley AR;Horseman ND
乳腺微环境可以延缓或加速与潜伏性癌症进展相关的事件。然而，在乳腺癌的背景下，当地的生理介质的行动知之甚少。5-羟色胺（5-HT）是乳腺和其他器官上皮细胞稳态的关键局部调节剂。在此，我们报告复杂的改变，在内在的乳腺血清素系统的人乳腺癌。采用色氨酸羟化酶1（TPH 1）免疫组织化学法分析了人乳腺肿瘤组织微阵列中5-羟色胺的生物合成能力。使用Oncomine数据库分析人乳腺肿瘤中的5-羟色胺受体（5-HT 1 -7）。5-羟色胺受体的表达，信号转导，和5-羟色胺对乳腺癌细胞表型的影响进行了比较，在非转化和转化的人乳腺细胞。在正常乳腺的情况下，5-HT在一定程度上通过促进生长停滞和细胞死亡来充当哺乳和退化的生理调节剂。这种严格调控的5-HT系统在人类乳腺癌中以多种方式被破坏。具体而言，TPH 1表达在进展期间经历非线性变化，在恶性进展期间表达增加。相应地，5-HT受体的严格调节模式在人乳腺癌细胞中变得失调，导致某些亚型的异位表达和其他亚型的抑制。受体表达的变化伴随着人乳腺癌细胞中5-HT受体下游信号的改变，导致对5-HT诱导的细胞凋亡的抗性，并刺激增殖。我们的数据构成了5-HT直接参与人类乳腺癌的第一份报告。5-HT生物合成能力的增加伴随着5-HT受体表达和信号传导的多种变化，有利于人乳腺癌细胞的恶性进展（例如，刺激增殖，不适当的细胞存活）。这是通过5-羟色胺从正常乳腺上皮的稳态调节机制中解偶联而发生的。这些发现为识别诊断和预后标志物开辟了新的途径，并为管理乳腺癌开辟了有价值的新治疗靶点。
The breast microenvironment can either retard or accelerate the events associated with progression of latent cancers. However, the actions of local physiological mediators in the context of breast cancers are poorly understood. Serotonin (5-HT) is a critical local regulator of epithelial homeostasis in the breast and other organs. Herein, we report complex alterations in the intrinsic mammary gland serotonin system of human breast cancers. Serotonin biosynthetic capacity was analyzed in human breast tumor tissue microarrays using immunohistochemistry for tryptophan hydroxylase 1 (TPH1). Serotonin receptors (5-HT1-7) were analyzed in human breast tumors using the Oncomine database. Serotonin receptor expression, signal transduction, and 5-HT effects on breast cancer cell phenotype were compared in non-transformed and transformed human breast cells. In the context of the normal mammary gland, 5-HT acts as a physiological regulator of lactation and involution, in part by favoring growth arrest and cell death. This tightly regulated 5-HT system is subverted in multiple ways in human breast cancers. Specifically, TPH1 expression undergoes a non-linear change during progression, with increased expression during malignant progression. Correspondingly, the tightly regulated pattern of 5-HT receptors becomes dysregulated in human breast cancer cells, resulting in both ectopic expression of some isoforms and suppression of others. The receptor expression change is accompanied by altered downstream signaling of 5-HT receptors in human breast cancer cells, resulting in resistance to 5-HT-induced apoptosis, and stimulated proliferation. Our data constitutes the first report of direct involvement of 5-HT in human breast cancer. Increased 5-HT biosynthetic capacity accompanied by multiple changes in 5-HT receptor expression and signaling favor malignant progression of human breast cancer cells (for example, stimulated proliferation, inappropriate cell survival). This occurs through uncoupling of serotonin from the homeostatic regulatory mechanisms of the normal mammary epithelium. The findings open a new avenue for identification of diagnostic and prognostic markers, and valuable new therapeutic targets for managing breast cancer.
登录
查看更多内容
影响因子：
8
作者：
Farmer, P;Bonnefoi, H;Iggo, R
通讯作者：
Iggo, R
DOI：
10.1186/bcr1385
发表时间：
2006
期刊：
Breast cancer research : BCR
影响因子：
--
作者：
Chang CC
通讯作者：
Chang CC
影响因子：
3.5
作者：
Hernandez, L. L.;Stiening, C. M.;Collier, R. J.
通讯作者：
Collier, R. J.
影响因子：
64.8
作者：
Bild, AH;Yao, G;Nevins, JR
通讯作者：
Nevins, JR
DOI：
10.1038/newbio239161a0
发表时间：
1972-01-01
期刊：
NATURE-NEW BIOLOGY
影响因子：
--
作者：
BURGER, MM;BRECKENRIDGE, BM;SHEPPARD, JR
通讯作者：
SHEPPARD, JR