The interaction between
breast tumor epithelial and stromal cells is vital for initial and recurrent
tumor growth. While
breast cancer-associated stromal cells provide a favorable environment for proliferation and
metastasis, the molecular mechanisms contributing to this process are not fully understood.
Nuclear receptors (NRs) are intracellular
transcription factors that directly regulate gene expression. Little is known about the status of NRs in
cancer-associated stroma.
Nuclear Receptor Low-Density Taqman Arrays were used to compare the gene expression profiles of all 48 NR family members in a collection of primary cultured cancer-associated fibroblasts (CAFs) obtained from
estrogen receptor (ER)α positive breast
cancers (n = 9) and normal breast adipose fibroblasts (NAFs) (n = 7). Thirty-three of 48 NRs were expressed in both the groups, while 11 NRs were not detected in either. Three NRs (
dosage-sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX-1);
estrogen-related receptor beta (ERR-β); and RAR-related orphan receptor beta (ROR-β)) were only detected in NAFs, while one NR (liver receptor homolog-1 (LRH-1)) was unique to CAFs. Of the NRs co-expressed, four were significantly down-regulated in CAFs compared with NAFs (RAR-related orphan receptor-α (ROR-α);
Thyroid hormone receptor-β (TR-β);
vitamin D receptor (VDR); and
peroxisome proliferator-activated receptor-γ (
PPAR-γ)). Quantitative immunohistochemistry for LRH-1, TR-β, and
PPAR-γ
proteins in stromal fibroblasts from an independent panel of breast
cancers (ER-positive (n = 15), ER-negative (n = 15), normal (n = 14)) positively correlated with
mRNA expression profiles. The differentially expressed NRs identified in
tumor stroma are key mediators in
aromatase regulation and subsequent
estrogen production. Our findings reveal a distinct pattern of NR expression that therefore fits with a sustained and increased local
estrogen microenvironment in ER-positive
tumors. NRs in CAFs may provide a new avenue for the development of intratumoral-targeted
therapies in
breast cancer.