microRNA-205 regulates HER3 in human breast cancer.
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.
Iorio
Marilena V
MV
Molecular Biology Unit, Department of Experimental Oncology, Fondazione Istituto Di Ricovero e Cura a Carattere Scientifico, Istituto Nazionale Tumori, Milano, Italy.
Casalini
Patrizia
P
Piovan
Claudia
C
Di Leva
Gianpiero
G
Merlo
Andrea
A
Triulzi
Tiziana
T
Ménard
Sylvie
S
Croce
Carlo M
CM
Tagliabue
Elda
E
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
D000077156:Gefitinib; D000077341:Lapatinib; D035683:MicroRNAs; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D011799:Quinazolines; D020893:Receptor, ErbB-3; C534425:MIR205, human