Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

Frogne, Thomas; Benjaminsen, Rikke Vicki; Sonne-Hansen, Katrine; Sørensen, Boe Sandahl; Nexø, Ebba; Lænkholm, Anne‐Vibeke; Rasmussen, Louise Maymann; Riese, David J.; Crémoux, Patricia de; Stenvang, Jan; Lykkesfeldt, Annè E.

doi:10.1007/s10549-008-0011-8

Cited by 133 publications

(118 citation statements)

References 46 publications

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“…In addition, because it is known that phosphorylation of ERK1/2 can be also dependent on FAK activation [58], it is possible that FAK cleavage, induced by co-treatment, could play a role in ERK1/2 inhibition and BimEL activation. Finally, in agreement with the observations of Frogne et al [46], we demonstrated that MCF7 cells express low levels of EGFR, phospho-EGFR and phospho-ERK1/2. SAHA/TRAIL co-treatment markedly reduced the levels of these factors and concomitantly increased the dephosphorylated form of BimEL, thus suggesting that also in MCF-7 cells downregulation of EGFR can be correlated with accumulation of the active form of BimEL.…”

Section: Discussionsupporting

confidence: 93%

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SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

et al. 2012

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a b s t r a c t SAHA, an inhibitor of histone deacetylase activity, has been shown to sensitize tumor cells to apoptosis induced by TRAIL, a member of TNF-family. In this paper we investigated the effect of SAHA/TRAIL combination in two breast cancer cell lines, the ERaÀpositive MCF-7 and the ERaÀnegative MDA-MB231. Treatment of MDA-MB231 and MCF-7 cells with SAHA in combination with TRAIL caused detachment of cells followed by anoikis, a form of apoptosis which occurs after cell detachment, while treatment with SAHA or TRAIL alone did not produce these effects. The effects were more evident in MDA-MB231 cells, which were chosen for ascertaining the mechanism of SAHA/TRAIL action. Our results show that SAHA decreased the level of c-FLIP, thus favouring the interaction of TRAIL with the specific death receptors DR4 and DR5 and the consequent activation of caspase-8. These effects increased when the cells were treated with SAHA/TRAIL combination. Because z-IEDT-fmk, an inhibitor of caspase-8, prevented both the cleavage of the focal adhesion-kinase FAK and cell detachment, we suggest that activation of caspase-8 can be responsible for both the decrement of FAK and the consequent cell detachment. In addition, treatment with SAHA/TRAIL combination caused dissipation of DJ m , activation of caspase-3 and decrement of both phospho-EGFR and phospho-ERK1/2, a kinase which is involved in the phosphorylation of BimEL. Therefore, co-treatment also induced decrement of phospho-BimEL and a concomitant increase in the dephosphorylated form of BimEL, which plays an important role in the induction of anoikis.Our findings suggest the potential application of SAHA in combination with TRAIL in clinical trials for breast cancer.

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Section: Discussionsupporting

confidence: 93%

“…5A, high levels of both EGFR and phospho-ERK1/2 were detected in untreated MDA-MB231 cells, while in MCF-7, in agreement with the observation of Frogne et al [46], low levels of these proteins were found. The treatment reduced the levels of EGFR, phospho-EGFR and phospho-ERK1/2.…”

Section: Down-regulation Of Egfr Plays a Role In Anoikis Induced By Ssupporting

confidence: 90%

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

et al. 2012

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“…Unlike ErbB1 and ErbB2, ErbB3 does not require adaptor proteins to interact with the regulatory p85 subunit of PI3K, instead interacting directly through up to 6 potential phosphotyrosines. Consequently, ErbB3 activation proficiently triggers PI3K signaling and activation of this pathway is frequently observed in tumors that escape from currently marketed ErbB-directed inhibitors (4,6,8,27), as well as hormonal therapy (28,29) and chemotherapy (30,31). Thus, inhibition of ErbB3 activation by heregulin is a worthy therapeutic strategy that is being actively pursued (16,17).…”

Section: Discussionmentioning

confidence: 99%

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

McDonagh

Huhalov

Harms

et al. 2012

Molecular Cancer Therapeutics

256

204

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The prevalence of ErbB2 amplification in breast cancer has resulted in the heavy pursuit of ErbB2 as a therapeutic target. Although both the ErbB2 monoclonal antibody trastuzumab and ErbB1/ErbB2 dual kinase inhibitor lapatinib have met with success in the clinic, many patients fail to benefit. In addition, the majority of patients who initially respond will unfortunately ultimately progress on these therapies. Activation of ErbB3, the preferred dimerization partner of ErbB2, plays a key role in driving ErbB2-amplified tumor growth, but we have found that current ErbB2-directed therapies are poor inhibitors of ligand-induced activation. By simulating ErbB3 inhibition in a computational model of ErbB2/ErbB3 receptor signaling, we predicted that a bispecific antibody that docks onto ErbB2 and subsequently binds to ErbB3 and blocks ligand-induced receptor activation would be highly effective in ErbB2-amplified tumors, with superior activity to a monospecific ErbB3 inhibitor. We have developed a bispecific antibody suitable for both large scale production and systemic therapy by generating a single polypeptide fusion protein of two human scFv antibodies linked to modified human serum albumin. The resulting molecule, MM-111, forms a trimeric complex with ErbB2 and ErbB3, effectively inhibiting ErbB3 signaling and showing antitumor activity in preclinical models that is dependent on ErbB2 overexpression. MM-111 can be rationally combined with trastuzumab or lapatinib for increased antitumor activity and may in the future complement existing ErbB2-directed therapies to treat resistant tumors or deter relapse. Mol Cancer Ther; 11(3); 582-93. Ó2012 AACR.

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“…Several preclinical studies of fulvestrant resistance have reported changes in the ErbB system, consisting of the EGF receptor (EGFR/ HER1), ErbB2 (HER2/neu), ErbB3 (HER3), and ErbB4 (HER4) receptors and at least 12 activating ligands. The changes correlated with fulvestrant resistance have been observed at the ErbB receptor level, the ligand level, and in ErbB downstream signaling molecules [5][6][7][8][9][10][11]. Consequently, therapies targeting the ErbB system represent an attractive strategy in breast cancer treatment.…”

Section: Introductionmentioning

confidence: 99%

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

Sonne-Hansen

Norrie

Emdal

et al. 2009

Breast Cancer Res Treat

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Activation of ErbB3, EGFR and Erk is essential for growth of human breast cancer cell lines with acquired resistance to fulvestrant

Abstract: Seven fulvestrant resistant cell lines derived from the estrogen receptor α positive MCF-7 human breast cancer cell line were used to investigate the importance of epidermal growth factor receptor (ErbB1-4) signaling. We found an increase in mRNA expression of EGFR and the ErbB3/ErbB4

Cited by 133 publications

References 46 publications

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

SAHA/TRAIL combination induces detachment and anoikis of MDA-MB231 and MCF-7 breast cancer cells

Antitumor Activity of a Novel Bispecific Antibody That Targets the ErbB2/ErbB3 Oncogenic Unit and Inhibits Heregulin-Induced Activation of ErbB3

Breast cancer cells can switch between estrogen receptor α and ErbB signaling and combined treatment against both signaling pathways postpones development of resistance

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