title: microRNA-205 regulates HER3 in human breast cancer.
abstract: An increasing amount of experimental evidence shows that microRNAs can have a causal role in breast cancer tumorigenesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. HER2 overexpression is a hallmark of a particularly aggressive subset of breast tumors, and its activation is strictly dependent on the trans-interaction with other members of HER family; in particular, the activation of the PI3K/Akt survival pathway, so critically important in tumorigenesis, is predominantly driven through phosphorylation of the kinase-inactive member HER3. Here, we show that miR-205, down-modulated in breast tumors compared with normal breast tissue, directly targets HER3 receptor, and inhibits the activation of the downstream mediator Akt. The reintroduction of miR-205 in SKBr3 cells inhibits their clonogenic potential and increases the responsiveness to tyrosine-kinase inhibitors Gefitinib and Lapatinib, abrogating the HER3-mediated resistance and restoring a potent proapoptotic activity. Our data describe miR-205 as a new oncosuppressor gene in breast cancer, able to interfere with the proliferative pathway mediated by HER receptor family. Our study also provides experimental evidence suggesting that miR-205 can improve the responsiveness to specific anticancer therapies.
authors.affiliation: Molecular Biology Unit, Department of Experimental Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milano, Italy.
authors.forename: Marilena V
authors.initials: MV
authors.lastname: Iorio
authors.forename: Patrizia
authors.initials: P
authors.lastname: Casalini
authors.forename: Claudia
authors.initials: C
authors.lastname: Piovan
authors.forename: Gianpiero
authors.initials: G
authors.lastname: Di Leva
authors.forename: Andrea
authors.initials: A
authors.lastname: Merlo
authors.forename: Tiziana
authors.initials: T
authors.lastname: Triulzi
authors.forename: Sylvie
authors.initials: S
authors.lastname: Ménard
authors.forename: Carlo M
authors.initials: CM
authors.lastname: Croce
authors.forename: Elda
authors.initials: E
authors.lastname: Tagliabue
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D000077156:Gefitinib; D016147:Genes, Tumor Suppressor; D015316:Genetic Therapy; D006801:Humans; D000077341:Lapatinib; D035683:MicroRNAs / Q000235:genetics*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors / Q000235:genetics*; D014162:Transfection
chemical_list: D000077156:Gefitinib; D000077341:Lapatinib; D035683:MicroRNAs; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D020893:Receptor, ErbB-3; C534425:MIR205, human