TY - JOUR
T1 - MicroRNA-205 regulates HER3 in human breast cancer
AU - Iorio, Marilena V.
AU - Casalini, Patrizia
AU - Piovan, Claudia
AU - Leva, Gianpiero Di
AU - Merlo, Andrea
AU - Triulzi, Tiziana
AU - Ménard, Sylvie
AU - Croce, Carlo M.
AU - Tagliabue, Elda
PY - 2009/3/15
Y1 - 2009/3/15
N2 - An increasing amount of experimental evidence shows that microBNAs can have a causal role in breast cancer tumori- genesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. HER2 over- expression 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.
AB - An increasing amount of experimental evidence shows that microBNAs can have a causal role in breast cancer tumori- genesis as a novel class of oncogenes or tumor suppressor genes, depending on the targets they regulate. HER2 over- expression 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.
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U2 - 10.1158/0008-5472.CAN-08-2920
DO - 10.1158/0008-5472.CAN-08-2920
M3 - Article
C2 - 19276373
AN - SCOPUS:65549110881
VL - 69
SP - 2195
EP - 2200
JO - Journal of Cancer Research
JF - Journal of Cancer Research
SN - 0008-5472
IS - 6
ER -