title: Distinct nuclear receptor expression in stroma adjacent to breast tumors.
abstract: 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.
authors.forename: Kevin C
authors.initials: KC
authors.lastname: Knower
authors.forename: Ashwini L
authors.initials: AL
authors.lastname: Chand
authors.forename: Natalie
authors.initials: N
authors.lastname: Eriksson
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takagi
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Miki
authors.forename: Hironobu
authors.initials: H
authors.lastname: Sasano
authors.forename: Jane E
authors.initials: JE
authors.lastname: Visvader
authors.forename: Geoffrey J
authors.initials: GJ
authors.lastname: Lindeman
authors.forename: John W
authors.initials: JW
authors.lastname: Funder
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Fuller
authors.forename: Evan R
authors.initials: ER
authors.lastname: Simpson
authors.forename: Wayne D
authors.initials: WD
authors.lastname: Tilley
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Leedman
authors.forename: J  Dinny
authors.initials: J
authors.lastname: Graham
authors.forename: George E  O
authors.initials: GE
authors.lastname: Muscat
authors.forename: Christine L
authors.initials: CL
authors.lastname: Clarke
authors.forename: Colin D
authors.initials: CD
authors.lastname: Clyne
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D060787:Neoplasm Grading; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D012307:Risk Factors; D017154:Stromal Cells / Q000378:metabolism*
chemical_list: D018719:Erb-b2 Receptor Tyrosine Kinases; D018160:Receptors, Cytoplasmic and Nuclear; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone