Modulation of Nuclear Receptor Functions in Breast and Pancreatic Cancers

Date

2015-05

Journal Title

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Abstract

Alcohol Regulates Genes that are Associated with Response to Endocrine Therapy and Attenuates the Actions of Tamoxifen in Breast Cancer Cells. Pancreatic ductal adenocarcinoma (PDAC) is difficult to detect early and is often resistant to standard chemotherapeutic options, contributing to extremely poor disease outcomes. Members of the nuclear receptor superfamily carry out essential biological functions such as hormone signaling and are successfully targeted in the treatment of endocrine-related malignancies. Liver X receptors (LXRs) are nuclear receptors that regulate cholesterol homeostasis, lipid metabolism, and inflammation. Intriguingly, LXR agonists exhibit antiproliferative activity in diverse types of cancer cells. In this study, LXR agonist treatments disrupted proliferation, cell-cycle progression, and colony-formation of PDAC cells. At the molecular level, treatments downregulated expression of proteins involved in cell cycle progression and growth factor signaling. Microarray experiments further revealed changes in expression profiles of multiple gene networks involved in biological processes and pathways essential for cell growth and proliferation following LXR activation. These results establish the antiproliferative effects of LXR agonists and potential mechanisms of action in PDAC cells and provide evidence for their potential application in the prevention and treatment of PDAC. The Antiproliferative Properties and Mechanisms of LXR Ligands on Pancreatic Ductal Adenocarcinoma Cells. Hereditary, hormonal, and behavioral factors contribute to the development of breast cancer. One modifiable behavioral factor, alcohol consumption, is linked to breast cancer risk. In this study we characterized molecular mechanisms of action of alcohol in estrogen receptor (ER)-positive breast cancer cells. Treatments with alcohol promoted cell proliferation, increased growth factor signaling, and up-regulated the transcription of the ER target gene GREB1. Microarray analysis following alcohol treatment identified a large number of alcohol-responsive genes, which were strongly associated with clinical outcomes in patients who received endocrine therapy. Correspondingly, alcohol treatment attenuated the anti-proliferative effects of the endocrine therapeutic drug tamoxifen in ER-positive breast cancer cells. To determine the contribution and functions of responsive genes, their differential expression in tumors were assessed between outcome groups. The proto-oncogene BRAF was identified as a novel alcohol- and estrogen-induced gene that showed higher expression in patients with poor outcomes. Knock-down of BRAF, moreover, prevented the proliferation of breast cancer cells. These findings not only highlight the mechanistic basis of the effects of alcohol on breast cancer cells and increased risks for disease incidents and recurrence, but may facilitate the discovery and characterization of novel oncogenic pathways and markers in breast cancer research and therapeutics.

Description

Keywords

LXR, Pancreatic cancer, ER, Breast cancer, Alcohol

Citation

Portions of this document appear in: Candelaria, Nicholes R., Sridevi Addanki, Jine Zheng, Trang Nguyen-Vu, Husna Karaboga, Prasenjit Dey, Chiara Gabbi et al. "Antiproliferative effects and mechanisms of liver X receptor ligands in pancreatic ductal adenocarcinoma cells." PloS one 9, no. 9 (2014): e106289. And in: Nguyen-Vu, Trang, Lise-Lotte Vedin, Ka Liu, Philip Jonsson, Jean Z. Lin, Nicholes R. Candelaria, Lindsay P. Candelaria et al. "Liver× receptor ligands disrupt breast cancer cell proliferation through an E2F-mediated mechanism." Breast cancer research 15, no. 3 (2013): R51. And in: Candelaria, Nicholes R., Ka Liu, and Chin‐Yo Lin. "Estrogen receptor alpha: Molecular mechanisms and emerging insights." Journal of cellular biochemistry 114, no. 10 (2013): 2203-2208.