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Open Access Highly Accessed Research article

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

Vaibhav P Pai124, Aaron M Marshall12, Laura L Hernandez1, Arthur R Buckley3 and Nelson D Horseman12*

Author Affiliations

1 Department of Molecular and Cellular Physiology, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0576, USA

2 Systems Biology and Physiology Program, University of Cincinnati, 231 Albert Sabin Way, Cincinnati, OH, 45267-0576, USA

3 James L. Winkle College of Pharmacy, University of Cincinnati, 3225 Eden Ave, Cincinnati, OH, 45267-0004, USA

4 Current address: Tufts Center for Regenerative and Developmental Biology and Biology Department, Tufts University, 200 Boston Ave, Medford, MA, 02155, USA

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Breast Cancer Research 2009, 11:R81  doi:10.1186/bcr2448

Published: 10 November 2009

Abstract

Introduction

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.

Methods

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.

Results

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.

Conclusions

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.