title: MicroRNA networks regulated by all-trans retinoic acid and Lapatinib control the growth, survival and motility of breast cancer cells.
abstract: SKBR3-cells, characterized by ERBB2/RARA co-amplification, represent a subgroup of HER2+ breast-cancers sensitive to all-trans retinoic acid (ATRA) and Lapatinib. In this model, the two agents alone or in combination modulate the expression of 174 microRNAs (miRs). These miRs and predicted target-transcripts are organized in four interconnected modules (Module-1 to -4). Module-1 and Module-3 consist of ATRA/Lapatinib up-regulated and potentially anti-oncogenic miRs, while Module-2 contains ATRA/Lapatinib down-regulated and potentially pro-oncogenic miRs. Consistent with this, the expression levels of Module-1/-3 and Module-2 miRs are higher and lower, respectively, in normal mammary tissues relative to ductal-carcinoma-in-situ, invasive-ductal-carcinoma and metastases. This indicates associations between tumor-progression and the expression profiles of Module-1 to -3 miRs. Similar associations are observed with tumor proliferation-scores, staging, size and overall-survival using TCGA (The Cancer Genome Atlas) data. Forced expression of Module-1 miRs, (miR-29a-3p; miR-874-3p) inhibit SKBR3-cell growth and Module-3 miRs (miR-575; miR-1225-5p) reduce growth and motility. Module-2 miRs (miR-125a; miR-193; miR-210) increase SKBR3 cell growth, survival and motility. Some of these effects are of general significance, being replicated in other breast cancer cell lines representing the heterogeneity of this disease. Finally, our study demonstrates that HIPK2-kinase and the PLCXD1-phospholipase-C are novel targets of miR-193a-5p/miR-210-3p and miR-575/miR-1225-5p, respectively.
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: James Neil
authors.initials: JN
authors.lastname: Fisher
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Mineko
authors.initials: M
authors.lastname: Terao
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Maddalena
authors.initials: M
authors.lastname: Fratelli
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Mami
authors.initials: M
authors.lastname: Kurosaki
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Paroni
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Adriana
authors.initials: A
authors.lastname: Zanetti
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Gianni
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Marco
authors.initials: M
authors.lastname: Bolis
authors.affiliation: Department of Oncology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lupi
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia and Department of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: Tsykin
authors.affiliation: Centre for Cancer Biology, SA Pathology, Adelaide, Australia and Department of Medicine, University of Adelaide, Adelaide, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Goodall
authors.affiliation: Laboratory of Molecular Biology, IRCCS-Istituto di Ricerche Farmacologiche "Mario Negri", Milano, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Garattini
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D048708:Cell Growth Processes / Q000187:drug effects*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects*; D005260:Female; D006801:Humans; D000077341:Lapatinib; D035683:MicroRNAs / Q000187:drug effects* / Q000378:metabolism; D054801:Phosphoinositide Phospholipase C / Q000378:metabolism; D016133:Polymerase Chain Reaction; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000187:drug effects; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D002352:Carrier Proteins; D000077341:Lapatinib; D035683:MicroRNAs; D054801:Phosphoinositide Phospholipase C; D017346:Protein Serine-Threonine Kinases; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin; C000607071:RARA protein, human; C115114:HIPK2 protein, human; C508053:ERBB2 protein, human
keywords: breast cancer; lapatinib; microRNA; network analysis; retinoic acid