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.
Highlights
estrogen receptor (ER)-positive disease is the most common type of breast cancer, accounting for nearly 75% of all cases
We demonstrate that acquired resistance to long-term estrogen deprivation (LTED) in ER-positive breast cancer is abrogated by combination of fulvestrant and dasatinib, which together inhibits multiple biological phenotypes, including acinar formation, cell survival and invasion as well as cell proliferation in vitro and vivo
Since LTED cells in 3-D culture exhibit increased proliferation and formation of abnormal acini structures compared with parental controls, we further explored the effects of fulvestrant, dasatinib and MK0646 as single agents or combinations on mammary acinar formation and morphogenesis
Summary
ER-positive disease is the most common type of breast cancer, accounting for nearly 75% of all cases. We previously established long-term estrogen deprivation (LTED) in ERpositive breast cancer cell lines, which models endocrine therapy-resistant breast cancer [17] Using these cell lines as models, we demonstrated enhancement of InsR/IGF-1R pathway in LTED ER-positive cells. Inhibition of InsR and IGF-IR suppressed cell growth, the effect increased when combined with fulvestrant [17, 18], a second-line, pure ER antagonist that destroys the receptor without any agonist effect [21, 22]. This didn’t inhibit the invasion of LTED cells [17,18,19]
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