Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Spanheimer, Philip M.; Park, Jung Min; Askeland, Ryan W.; Kulak, Mikhail V.; Woodfield, George W.; Andrade, James P. De; Cyr, Anthony R.; Sugg, Sonia L.; Thomas, Alexandra; Weigel, Ronald J.

doi:10.1158/1078-0432.ccr-13-2221

Cited by 41 publications

(56 citation statements)

References 48 publications

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“…In the luminal MCF-7 and BT-474 cell lines, transient knockdown of RET reduced in vitro cell proliferation, which was implicated to occur through changes in the MAP kinase pathway, as knockdown of RET led to reduced levels of phosphorylated extracellular-signal-regulated kinases (p-ERK) (12). We compared the effect of knockdown of RET and EGFR alone and in combination.…”

Section: Resultsmentioning

confidence: 99%

“…We have previously reported that vandetanib treatment of the luminal MCF-7 and BT-474 cells in vitro reduced cell proliferation (12). However, vandetanib has TKI activity that targets several RTKs including RET and EGFR.…”

Section: Resultsmentioning

confidence: 99%

“…Fresh primary breast cancer samples were obtained from BMER with the University of Iowa Tissue Procurement Center. Fresh tumors were minced finely, dissociated overnight with gentle collagenase/hyaluronidase (Stemcell Technologies: Vancouver, BC, Canada), and treated with control media, vandetanib at a final concentration of 10 μM, or PD153035, which is a selective EGFR inhibitor PD153035 (SelleckChem), at a final concentration of 10 μM before harvesting for protein as described previously (12, 16). …”

Section: Methodsmentioning

confidence: 99%

“…Recently, it has been shown that inhibiting the RET pathway augmented estrogen response, and the ability of the tyrosine kinase inhibitor (TKI) sunitinib to block ERK activation in primary breast cancers correlated with RET expression (12). Response to the TKI vandetanib was also found to be significantly reduced with knockdown of RET; however, TKIs such as vandetanib have activity against several RTKs that may drive breast cancer growth.…”

Section: Introductionmentioning

confidence: 99%

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EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

Andrade

Park

et al. 2016

Molecular Cancer Therapeutics

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Expression of TFAP2C in luminal breast cancer is associated with reduced survival and hormone resistance, partially explained through regulation of RET. TFAP2C also regulates EGFR in HER2 breast cancer. We sought to elucidate the regulation and functional role of EGFR in luminal breast cancer. We used gene knockdown (KD) and treatment with a tyrosine kinase inhibitor (TKI) in cell lines and primary cancer isolates to determine the role of RET and EGFR in regulation of p-ERK and tumorigenesis. KD of TFAP2C decreased expression of EGFR in a panel of luminal breast cancers and ChIP-seq confirmed that TFAP2C targets the EGFR gene. Stable KD of TFAP2C significantly decreased cell proliferation and tumor growth, mediated in part through EGFR. While KD of RET or EGFR reduced proliferation (31% and 34%, p < 0.01), combined KD reduced proliferation greater than either alone (52% reduction, p < 0.01). The effect of the TKI vandetanib on proliferation and tumor growth response of MCF-7 cells was dependent upon expression of TFAP2C and dual KD of RET and EGFR eliminated the effects of vandetanib. The response of primary luminal breast cancers to TKIs assessed by ERK activation established a correlation with expression of RET and EGFR. We conclude that TFAP2C regulates EGFR in luminal breast cancer. Response to vandetanib was mediated though the TFAP2C target genes EGFR and RET. Vandetanib may provide a therapeutic effect in luminal breast cancer, and RET and EGFR can serve as molecular markers for response.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

Andrade

Park

et al. 2016

Molecular Cancer Therapeutics

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“…Such an autoregulatory loop is intriguing and has to be taken into consideration for the development of new targeted therapies in BC [45].…”

Section: Discussionmentioning

confidence: 99%

210 Genetic and epigenetic factors affect RET gene expression in breast cancer cell lines and influence survival in patients

Griseri¹,

Garrone²,

Sardo³

et al. 2015

European Journal of Cancer

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Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

Hatem

Labiod

Château-Joubert

et al. 2016

Intl Journal of Cancer

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The receptor tyrosine kinase RET is implicated in the progression of luminal breast cancers (BC) but its role in estrogen receptor (ER) negative tumors is unknown. Here we investigated the expression of RET in breast cancer patients tumors and patient-derived xenografts (PDX) and evaluated the therapeutic potential of Vandetanib, a tyrosin kinase inhibitor with strong activity against RET, EGFR and VEGFR2, in ER negative breast cancer PDX. The RT-PCR analysis of RET expression in breast tumors of 446 patients and 57 PDX, showed elevated levels of RET in ER1 and HER21 subtypes and in a small subgroup of triple-negative breast cancers (TNBC). The activity of Vandetanib was tested in vivo in three PDX models of TNBC and one model of HER21 BC with different expression levels of RET and EGFR. Vandetanib induced tumor regression in PDX models with high expression of RET or EGFR. The effect was associated with inhibition of RET/EGFR phosphorylation and MAP kinase pathway and increased necrosis. In a PDX model with no expression of RET nor EGFR, Vandetanib slowed tumor growth without inducing tumor regression. In addition, treatment by Vandetanib decreased expression of murine Vegf receptors and the endothelial marker Cd31 in the four PDX models tested, suggesting inhibition of tumor vascularization. In summary, these preclinical results suggest that Vandetanib treatment could be useful for patients with ER negative breast cancers overexpressing Vandetanib's main targets.Breast cancers are heterogeneous, with a multitude of molecular alterations supporting their malignant progression. RET overexpression was found in 33% of ER1 tumors and 10% ER-tumors. 6 In addition, it has been shown that anti-RET therapies might be used in ER1 tumors to potentiate the effect of endocrine treatments in preclinical models. 7,8 In another study performed on 108 breast cancer patients, expression of RET was found in high percentages in HER21, triple-negative and ER positive tumors. 9 Therefore, RET seems to be a promising therapeutic target in breast cancer, irrespectively of molecular subtype. If RET has been mainly investigated in luminal breast cancer, no preclinical evidence exists that it is a relevant target in the subset of ER negative tumors overexpressing RET.

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Inhibition of RET Increases the Efficacy of Antiestrogen and Is a Novel Treatment Strategy for Luminal Breast Cancer

Cited by 41 publications

References 48 publications

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

EGFR Is Regulated by TFAP2C in Luminal Breast Cancer and Is a Target for Vandetanib

210 Genetic and epigenetic factors affect RET gene expression in breast cancer cell lines and influence survival in patients

Vandetanib as a potential new treatment for estrogen receptor‐negative breast cancers

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