title: Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer.
abstract: Despite numerous therapies that effectively inhibit estrogen signaling in breast cancer, a significant proportion of patients with estrogen receptor (ER)-positive malignancy will succumb to their disease. Herein we demonstrate that long-term estrogen deprivation (LTED) therapy among ER-positive breast cancer cells results in the adaptive increase in ER expression and subsequent activation of multiple tyrosine kinases. Combination therapy with the ER down-regulator fulvestrant and dasatinib, a broad kinase inhibitor, exhibits synergistic activity against LTED cells, by reduction of cell proliferation, cell survival, cell invasion and mammary acinar formation. Screening kinase phosphorylation using protein arrays and functional proteomic analysis demonstrates that the combination of fulvestrant and dasatinib inhibits multiple tyrosine kinases and cancer-related pathways that are constitutively activated in LTED cells. Because LTED cells display increased insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF-1R) signaling, we added an ant-IGF-1 antibody to the combination with fulvestrant and dasatinib in an effort to further increase the inhibition. However, adding MK0646 only modestly increased the inhibition of cell growth in monolayer culture, but neither suppressed acinar formation nor inhibited cell migration in vitro and invasion in vivo. Therefore, combinations of fulvestrant and dasatinib, but not MK0646, may benefit patients with tyrosine-kinase-activated, endocrine therapy-resistant breast cancer.
authors: Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Shuying
authors: S
authors: Liu
authors: Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Xiaolong
authors: X
authors: Meng
authors: Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Huiqin
authors: H
authors: Chen
authors: Bioinformatics and Computational Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Wenbin
authors: W
authors: Liu
authors: Department of Pharmacology and Toxicology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH. Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN.
authors: Todd
authors: T
authors: Miller
authors: University of Georgia College of Pharmacy, Athens, GA.
authors: Mandi
authors: M
authors: Murph
authors: Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Yiling
authors: Y
authors: Lu
authors: Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Fan
authors: F
authors: Zhang
authors: Veterinary Medicine and Surgery, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Mihai
authors: M
authors: Gagea
authors: Department of Cancer Biology, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN. Medicine, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN.
authors: Carlos L
authors: CL
authors: Arteaga
authors: Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Gordon B
authors: GB
authors: Mills
authors: Surgical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Funda
authors: F
authors: Meric-Bernstam
authors: Department of Breast Medical Oncology, The University of Texas, MD Anderson Cancer Center, Houston, TX. Systems Biology, The University of Texas, MD Anderson Cancer Center, Houston, TX.
authors: Ana M
authors: AM
authors: González-Angulo
mesh_terms: D061354:Acinar Cells / Q000187:drug effects; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D000069439:Dasatinib; D004357:Drug Synergism; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology; D004967:Estrogens / Q000096:biosynthesis*; D005260:Female; D000077267:Fulvestrant; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011743:Pyrimidines / Q000494:pharmacology; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D011960:Receptors, Estrogen / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D004967:Estrogens; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011960:Receptors, Estrogen; D013844:Thiazoles; D000077267:Fulvestrant; D004958:Estradiol; C569480:dalotuzumab; D011505:Protein-Tyrosine Kinases; D017526:Receptor, IGF Type 1; D000069439:Dasatinib