Department of Molecular and Cellular Physiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0576, USA.
Breast Cancer Res. 2009;11(6):R81. doi: 10.1186/bcr2448. Epub 2009 Nov 10.
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.
乳腺微环境既可延缓也可加速与潜伏癌进展相关的事件。然而，局部生理介质在乳腺癌中的作用仍知之甚少。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因子。在此，我们报道了人乳腺癌中固有乳腺 5-羟色胺系统的复杂改变。
使用色氨酸羟化酶 1（TPH1）的免疫组织化学法分析人乳腺癌组织微阵列中的 5-HT 生物合成能力。使用 Oncomine 数据库分析人乳腺癌中的 5-HT 受体（5-HT1-7）。比较非转化和转化的人乳腺细胞中 5-HT 受体表达、信号转导和 5-HT 对乳腺癌细胞表型的影响。
在正常乳腺中，5-HT 作为生理性乳汁分泌和退化的调节剂，部分通过促进生长停滞和细胞死亡起作用。这种受严格调控的 5-HT 系统在人乳腺癌中以多种方式被颠覆。具体来说，TPH1 表达在恶性进展过程中呈非线性变化，在恶性进展过程中表达增加。相应地，人乳腺癌细胞中受严格调控的 5-HT 受体模式变得失调，导致一些亚型的异位表达和其他亚型的抑制。受体表达变化伴随着人乳腺癌细胞中 5-HT 受体下游信号转导的改变，导致对 5-HT 诱导的细胞凋亡的抗性和增殖的刺激。
我们的数据首次报道了 5-HT 直接参与人乳腺癌。增加的 5-HT 生物合成能力伴随着 5-HT 受体表达和信号转导的多种变化，有利于人乳腺癌细胞的恶性进展（例如，刺激增殖、不当细胞存活）。这是通过将 5-HT 与正常乳腺上皮的稳态调节机制解耦来实现的。这些发现为识别诊断和预后标志物以及管理乳腺癌的有价值的新治疗靶点开辟了新途径。
