Dataset Information

Discovery dataset on tamoxifen treated Estrogen Receptor (ER) positive breast cancer patients

ABSTRACT: 56 estrogen receptor positive breast cancer tissues from patients treated with tamoxifen upon recurrence (32 Good outcome vs 24 Poor outcome) have been microdissected to obtain a pure population of epithelial tumor cells. Breast tumor enriched tissues have been sonicated and proteins have been in-solution digested and analyzed via a LTQ-Orbitrap coupled online with a nano-LC system. Thermo output .RAW files were analyzed through MaxQuant (version 1.4.1.2) using the human proteome FASTA (version 2012-09, human canonical proteome) as search library.

INSTRUMENT(S): LTQ Orbitrap

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Tommaso De Marchi

LAB HEAD: Tommaso De Marchi

PROVIDER: PXD000484 | Pride | 2015-08-21

REPOSITORIES: Pride

ACCESS DATA

Dataset's files

Source:

			Action	DRS
	100820O2c1_MT-AU-0044-2010-08-1_030.RAW	Raw
	100820O2c1_MT-AU-0044-2010-08-2_034.RAW	Raw
	100820O2c1_MT-AU-0044-2010-08-3_038.RAW	Raw
	100820O2c1_MT-AU-0044-2010-08-4_044.RAW	Raw
	100820O2c1_MT-AU-0044-2010-08-5_048.RAW	Raw

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Publications

4-protein signature predicting tamoxifen treatment outcome in recurrent breast cancer.

De Marchi Tommaso T Liu Ning Qing NQ Stingl Cristoph C Timmermans Mieke A MA Smid Marcel M Look Maxime P MP Tjoa Mila M Braakman Rene B H RB Opdam Mark M Linn Sabine C SC Sweep Fred C G J FC Span Paul N PN Kliffen Mike M Luider Theo M TM Foekens John A JA Martens John W M JW Umar Arzu A

Molecular oncology 20150807 1

Estrogen receptor (ER) positive tumors represent the majority of breast malignancies, and are effectively treated with hormonal therapies, such as tamoxifen. However, in the recurrent disease resistance to tamoxifen therapy is common and a major cause of death. In recent years, in-depth proteome analyses have enabled identification of clinically useful biomarkers, particularly, when heterogeneity in complex tumor tissue was reduced using laser capture microdissection (LCM). In the current study, ...[more]

PMID: 26285647

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Project description:Tamoxifen, an antagonist to estrogen receptor (ER), is a first line drug used in breast cancer treatment. However, this therapy is complicated by the fact that a substantial number of patients exhibit either de novo or acquired resistance. To characterize the signaling mechanisms underlying the resistance to tamoxifen, we established a tamoxifen-resistant cell line by treating the MCF7 breast cancer cell line with tamoxifen for over 6 months. We showed that this cell line exhibited resistance to tamoxifen both in vitro and in vivo. In order to quantify the phosphorylation alterations associated with tamoxifen resistance, we performed SILAC-based quantitative phosphoproteomic profiling on the resistant and vehicle-treated sensitive cell lines where we identified >5,600 unique phosphopeptides. We found phosphorylation levels of 1,529 peptides were increased (>2 fold) and 409 peptides were decreased (<0.5-fold) in tamoxifen resistant cells compared to tamoxifen sensitive cells. Gene set enrichment analysis revealed that focal adhesion pathway was the top enriched signaling pathway activated in tamoxifen resistant cells. We observed hyperphosphorylation of the focal adhesion kinases FAK1 and FAK2 in the tamoxifen resistant cells. Of note, FAK2 was not only hyperphosphorylated but also transcriptionally upregulated in tamoxifen resistant cells. Suppression of FAK2 by specific siRNA knockdown could sensitize the resistant cells to the treatment of tamoxifen. We further showed that inhibiting FAK activity using the small molecule inhibitor PF562271 repressed cellular proliferation in vitro and tumor formation in vivo. More importantly, our survival analysis revealed that high expression of FAK2 significantly associated with short metastasis-free survival of ER-positive breast cancer patients treated with tamoxifen-based hormone therapy. Our studies suggest that FAK2 is a great potential target for the development of therapy for the treatment of hormone refractory breast cancers.