Altered serotonin physiology in human breast cancers favors paradoxical growth and cell survival

Abstract

IntroductionThe 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.MethodsSerotonin 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.ResultsIn 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.ConclusionsOur 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.

Biology of breast cancer during pregnancy using genomic profiling

“…It is synthesized within the breast epithelial cells during lactation and acts as a physiological regulator of involution following pregnancy, in part by favoring growth arrest and cell death (Marshall et al 2010). The application of serotonin to primary human epithelial cells was shown to suppress cell growth (Pai et al 2009). Conversely, serotonin was found to stimulate tumor growth when applied to invasive breast cancer cell lines, by promoting proliferation and epithelial-mesenchymal transition (Pai et al 2009).…”

“…The application of serotonin to primary human epithelial cells was shown to suppress cell growth (Pai et al 2009). Conversely, serotonin was found to stimulate tumor growth when applied to invasive breast cancer cell lines, by promoting proliferation and epithelial-mesenchymal transition (Pai et al 2009). Moreover, serotonin was found to induce the transcription of parathyroid hormone-related protein and the metastasis-associated transcription factor Runx2/Cbfal via the serotonin receptor, 5-HT2 (Hernandez et al 2012).…”

Mammary gland serotonin regulates parathyroid hormone-related protein and other bone-related signals

“…The mouse mammary epithelial cells (HC11) were maintained under growth medium conditions and lactogen induced by treatment of 3-day-confluent cultures with prolactin, insulin, and cortisol as previously described (18). MDA-MB-231, MCF7, and T47D breast cancer cell lines and MCF10A (normal human ductal mammary epithelial cell lines) were obtained from the American Type Culture Collection (ATCC) and cultured as previously described (31,38,49). pBMECs were obtained as a generous gift from Dr. Robert Collier, University of Arizona, and cultured as previously described (16,32).…”

“…The processes regulated by 5-HT include not only specialized mammary gland functions such as milk protein and milk lipid biogenesis but also fundamental cell biological processes (i.e., apoptosis, barrier permeability, cell shedding, etc.) (16,30,31,36,38,49). Epithelia lining other ductal/ alveolar secretory organs also possess local 5-HT signaling systems, which have been implicated in various aspects of epithelial homeostasis (39).…”

Serotonin Regulates β-Casein Expression <i>via</i> 5-HT₇ Receptors in Human Mammary Epithelial MCF-12A Cells

“…17) To investigate the expression levels of these 5-HT isoforms in MCF-12A cells with or without PRL treatment, RT-PCR and Western blot analysis were performed. mRNA expression of all four 5-HTR subtypes was detectable in untreated MCF-12A cells, and PRL treatment significantly enhanced the expression levels of 5-HTR 1D , 5-HTR 3A , and 5-HTR 7 mRNA (Fig.…”