title: Interaction between p53 and estradiol pathways in transcriptional responses to chemotherapeutics.
abstract: Estrogen receptors (ERs) and p53 can interact via cis-elements to regulate the angiogenesis-related VEGFR-1 (FLT1) gene, as we reported previously. Here, we address cooperation between these transcription factors on a global scale. Human breast adenocarcinoma MCF7 cells were exposed to single or combinatorial treatments with the chemotherapeutic agent doxorubicin and the ER ligand 17β-estradiol (E2). Whole-genome transcriptome changes were measured by expression microarrays. Nearly 200 differentially expressed genes were identified that showed limited responsiveness to either doxorubicin treatment or ER ligand alone but were upregulated in a greater than additive manner following combined treatment. Based on exposure to 5-fuorouracil and nutlin-3a, the combined responses were treatment-specific. Among 16 genes chosen for validation using quantitative real-time PCR, seven (INPP5D, TLR5, KRT15, EPHA2, GDNF, NOTCH1, SOX9) were confirmed to be novel direct targets of p53, based on responses in MCF7 cells silenced for p53 or cooperative targets of p53 and ER. Promoter pattern searches and chromatin IP experiments for the INPP5D, TLR5, KRT15 genes supported direct, cis-mediated p53 and/or ER regulation through canonical and noncanonical p53 and ER response elements. Collectively, we establish that combinatorial activation of p53 and ER can induce novel gene expression programs that have implications for cell-cell communications, adhesion, cell differentiation, development and inflammatory responses as well as cancer treatments.
authors.affiliation: Laboratory of Transcriptional Networks, Centre for Integrative Biology (CIBIO), University of Trento, Mattarello, Trento, Italy.
authors.forename: Mattia
authors.initials: M
authors.lastname: Lion
authors.forename: Alessandra
authors.initials: A
authors.lastname: Bisio
authors.forename: Toma
authors.initials: T
authors.lastname: Tebaldi
authors.forename: Veronica
authors.initials: V
authors.lastname: De Sanctis
authors.forename: Daniel
authors.initials: D
authors.lastname: Menendez
authors.forename: Michael A
authors.initials: MA
authors.lastname: Resnick
authors.forename: Yari
authors.initials: Y
authors.lastname: Ciribilli
authors.forename: Alberto
authors.initials: A
authors.lastname: Inga
mesh_terms: D015153:Blotting, Western; D004317:Doxorubicin / Q000494:pharmacology; D004958:Estradiol / Q000378:metabolism*; D005472:Fluorouracil; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007093:Imidazoles; D061986:MCF-7 Cells; D046228:Microarray Analysis; D010879:Piperazines; D060888:Real-Time Polymerase Chain Reaction; D013997:Time Factors; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: D007093:Imidazoles; D010879:Piperazines; D016159:Tumor Suppressor Protein p53; D004958:Estradiol; C482205:nutlin 3; D004317:Doxorubicin; D005472:Fluorouracil
keywords: 17-beta estradiol; MCF7 cells; cis-element; doxorubicin; estrogen receptor; non-canonical response elements; nutlin; p53; synergistic cooperation; synergy