Distinct Nuclear Receptor Expression Status Identified In Stroma Adjacent To ER-Positive Breast Tumors

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: MON 355-388-Sex Hormone Receptor Action & Reaction
Basic/Translational
Monday, June 17, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board MON-376
Kevin Christopher Knower*1, Ashwini L Chand2, Natalie Eriksson3, Kiyoshi Takagi4, Yasuhiro Miki5, Hironobu Sasano6, Jane Visvader7, Geoffrey Lindeman8, George E. O. Muscat9 and Colin D Clyne2
1Prince Henry's Institute, Melbourne, Australia, 2Prince Henry's Institute, Clayton VIC, Australia, 3Institute for Molecular Bioscience, University of Queensland, Queensland, Australia, 4Department of Pathology and Histotechnology, Tohoku University, 5Tohoku Univ Grad Schl of Dentist, Sendai, Japan, 6Tohoku Univ Sch of Med, Miyagi, Japan, 7The Walter & Eliza Jennings In, Parkville VIC, Australia, 8Walter Eliza Hall Institute, 9The Univ of QLD, St Lucia QLD, Australia
The interaction between breast tumor epithelial and stromal cells is vital for initial and recurrent tumor growth. The cancer-associated stroma is reprogrammed to provide the most favourable environment for tumor proliferation and metastasis. Furthermore, in post-menopausal women the stroma is the main source of local estrogen through increased activity of the key enzyme aromatase.  The extent of this reprogramming is poorly understood. Nuclear receptors (NRs) are intracellular transcription factors that directly regulate gene expression in response to lipophilic molecules. In the cellular context NRs regulate cell proliferation, differentiation and apoptosis mainly via the transcriptional regulation of target genes and as major points of convergence of multiple signal transduction pathways. Little is known about the status of NRs in tumor associated stroma. Here, we quantified all forty-eight NRs in normal breast adipose fibroblasts (NAFs) and breast cancer-associate fibroblasts (CAFs) in order to identify NRs differentially expressed between NAFs and CAFs.

Nuclear Receptor Low Density Taqman Arrays were used to compare the gene expression profiles in a collection of primary cultured CAFs (n=9) and NAFs (n=7). StatMiner Analytical software was used to perform Non-Parametric (Wilcoxon) tests while geNorm selected the most stable endogenous controls used for normalisation. Thirty-three of 48 NRs were expressed in both cohorts, while 11 NRs were not detected in either. Three (DAX-1, ERR-b and ROR-b) were only detected in NAFs, whilst one (LRH-1) was unique to CAFs. Of the NRs expressed, four showed significant down-regulation in CAFs compared to NAFs: RAR-related orphan receptor-a (ROR-a) (1.95-fold); Thyroid hormone receptor-b (TR-b) (15.63-fold); Vitamin D receptor (VDR) (1.91-fold); and Peroxisome proliferator-activated receptor-g (PPAR-g) (3.48-fold).

Stromal expression of NRs may be an important component in the cross-talk within the tumor microenvironment. Given the importance of aromatase expression in the breast tumor stroma, our findings reveal a pattern of NR expression that fits with a sustained and increased local estrogen microenvironment. The elucidation of molecular mechanisms and functional consequences of the differing expression profiles of NRs in CAFs may provide a new avenue for the development of intratumoral-targeted therapies in breast cancer.

Nothing to Disclose: KCK, ALC, NE, KT, YM, HS, JV, GL, GEOM, CDC

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: This work was supported by the National Health and Medical Research Council of Australia through fellowships to CDC (#338518); the Victoria Breast Cancer Research Consortium Inc.; the United States Department of Defense fellowship to ALC; a Collaborative Program Grant from the National Breast Cancer Foundation Australia; and the Victorian Government’s Operational Infrastructure Support Program.