TY - JOUR
T1 - Targeting tyrosine-kinases and estrogen receptor abrogates resistance to endocrine therapy in breast cancer
AU - Liu, Shuying
AU - Meng, Xiaolong
AU - Chen, Huiqin
AU - Liu, Wenbin
AU - Miller, Todd
AU - Murph, Mandi
AU - Lu, Yiling
AU - Zhang, Fan
AU - Gagea, Mihai
AU - Arteaga, Carlos L.
AU - Mills, Gordon B.
AU - Meric-Bernstam, Funda
AU - González-Angulo, Ana M.
PY - 2014
Y1 - 2014
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Dasatinib
KW - Fulvestrant
KW - MK0646
KW - Targeting therapy
UR - http://www.scopus.com/inward/record.url?scp=84910029848&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84910029848&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.2022
DO - 10.18632/oncotarget.2022
M3 - Article
C2 - 24979294
AN - SCOPUS:84910029848
SN - 1949-2553
VL - 5
SP - 9049
EP - 9064
JO - Oncotarget
JF - Oncotarget
IS - 19
ER -