Loss of Phosphatase and Tensin homologue deleted on chromosome 10 engages ErbB3 and insulin-like growth factor-I receptor signaling to promote antiestrogen resistance in breast cancer.
Knockdown of the tumor suppressor phosphatase Phosphatase and tensin homologue deleted on chromosome 10 (PTEN) with shRNA in three estrogen receptor (ER)-positive breast cancer cell lines resulted in increased phosphatidylinositol-3 kinase (PI3K) and AKT activities, resistance to tamoxifen and fulvestrant, and hormone-independent growth. PTEN knockdown induced the up-regulation of ER transcriptional activity in MCF-7 cells but decreased ER protein levels and transcriptional activity in T47D and MDA-361 cells. Tamoxifen and fulvestrant treatment inhibited estradiol-induced ER transcriptional activity in all shPTEN cell lines but did not abrogate the increased cell proliferation induced by PTEN knockdown. PTEN knockdown increased basal and ligand-induced activation of the insulin-like growth factor-I (IGF-I) and ErbB3 receptor tyrosine kinases, and prolonged the association of the p85 PI3K subunit with the IGF-I receptor (IGF-IR) effector insulin receptor substrate-1 and with ErbB3, implicating PTEN in the modulation of signaling upstream of PI3K. Consistent with these data, PTEN levels inversely correlated with levels of tyrosine-phosphorylated IGF-IR in tissue lysate arrays of primary breast cancers. Inhibition of IGF-IR and/or ErbB2-mediated activation of ErbB3 with tyrosine kinase inhibitors restored hormone dependence and the growth inhibitory effect of tamoxifen and fulvestrant on shPTEN cells, suggesting that cotargeting both ER and receptor tyrosine kinase pathways holds promise for the treatment of patients with ER+, PTEN-deficient breast cancers.
Department of Medicine, Vanderbilt-Ingram Comprehensive Cancer Center, Vanderbilt University, Nashville, TN 37232-6307, USA.
Todd W
TW
Miller
Marianela
M
Pérez-Torres
Archana
A
Narasanna
Marta
M
Guix
Olle
O
Stål
Gizeh
G
Pérez-Tenorio
Ana M
AM
Gonzalez-Angulo
Bryan T
BT
Hennessy
Gordon B
GB
Mills
J Phillip
JP
Kennedy
Craig W
CW
Lindsley
Carlos L
CL
Arteaga
D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D002455:Cell Division; D045744:Cell Line, Tumor; D002872:Chromosome Deletion; D002888:Chromosomes, Human, Pair 19; D019008:Drug Resistance, Neoplasm; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D051059:PTEN Phosphohydrolase / Q000172:deficiency*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000502:physiology; D020893:Receptor, ErbB-3 / Q000502:physiology*; D017526:Receptor, IGF Type 1 / Q000502:physiology*; D014158:Transcription, Genetic
D020847:Estrogen Receptor Modulators; D051059:PTEN Phosphohydrolase; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D017526:Receptor, IGF Type 1; C494929:PTEN protein, human