title: Differences in transcriptional effects of 1α,25 dihydroxyvitamin D3 on fibroblasts associated to breast carcinomas and from paired normal breast tissues.
abstract: The effects of 1α,25 dihydroxyvitamin D3 (1,25D) on breast carcinoma associated fibroblasts (CAFs) are still unknown. This study aimed to identify genes whose expression was altered after 1,25D treatment in CAFs and matched adjacent normal mammary associated fibroblasts (NAFs). CAFs and NAFs (from 5 patients) were cultured with or without (control) 1,25D 100 nM. Both CAF and NAF expressed vitamin D receptor (VDR) and 1,25D induction of the genomic pathway was detected through up-regulation of the target gene CYP24A1. Microarray analysis showed that despite presenting 50% of overlapping genes, CAFs and NAFs exhibited distinct transcriptional profiles after 1,25D treatment (FDR<0.05). Functional analysis revealed that in CAFs, genes associated with proliferation (NRG1, WNT5A, PDGFC) were down regulated and those involved in immune modulation (NFKBIA, TREM-1) were up regulated, consistent with anti tumor activities of 1,25D in breast cancer. In NAFs, a distinct subset of genes was induced by 1,25D, involved in anti apoptosis, detoxification, antibacterial defense system and protection against oxidative stress, which may limit carcinogenesis. Co-expression network and interactome analysis of genes commonly regulated by 1,25D in NAFs and CAFs revealed differences in their co-expression values, suggesting that 1,25D effects in NAFs are distinct from those triggered in CAFs.
authors.affiliation: Departamento de Radiologia e Oncologia, Faculdade de Medicina da Universidade de São Paulo, Av. Dr. Arnaldo, 455, Sala 4112, CEP 01246-903, São Paulo, SP, Brazil.
authors.forename: Laura Tojeiro
authors.initials: LT
authors.lastname: Campos
authors.forename: Helena
authors.initials: H
authors.lastname: Brentani
authors.forename: Rosimeire Aparecida
authors.initials: RA
authors.lastname: Roela
authors.forename: Maria Lucia Hirata
authors.initials: ML
authors.lastname: Katayama
authors.forename: Leandro
authors.initials: L
authors.lastname: Lima
authors.forename: Cíntia Flores
authors.initials: CF
authors.lastname: Rolim
authors.forename: Cíntia
authors.initials: C
authors.lastname: Milani
authors.forename: Maria Aparecida Azevedo Koike
authors.initials: MA
authors.lastname: Folgueira
authors.forename: Maria Mitzi
authors.initials: MM
authors.lastname: Brentani
mesh_terms: D000328:Adult; D001940:Breast / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D002117:Calcitriol / Q000494:pharmacology*; D018270:Carcinoma, Ductal, Breast / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D053263:Gene Regulatory Networks / Q000187:drug effects; D006801:Humans; D008875:Middle Aged; D059467:Transcriptome / Q000187:drug effects; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000187:drug effects / Q000235:genetics
chemical_list: D002117:Calcitriol