PXD001812

PXD001812 is an original dataset announced via ProteomeXchange.

Title	Phosphoproteomic analysis of tamoxifen resistant breast cancer
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.
HostingRepository	PRIDE
AnnounceDate	2016-05-25
AnnouncementXML	Submission_2016-05-25_08:52:12.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Muhammad Zahari
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	6x(13)C: 4x(15)N labeled L-arginine; monohydroxylated residue; iodoacetamide derivatized residue; phosphorylated residue; 6x(13)C: 2x(15)N labeled L-lysine
Instrument	LTQ Orbitrap Velos

Revision	Datetime	Status	ChangeLog Entry
0	2015-02-13 01:11:48	ID requested
⏵ 1	2016-05-25 08:52:13	announced

Wu X, Zahari MS, Renuse S, Nirujogi RS, Kim MS, Manda SS, Stearns V, Gabrielson E, Sukumar S, Pandey A, Phosphoproteomic Analysis Identifies Focal Adhesion Kinase 2 (FAK2) as a Potential Therapeutic Target for Tamoxifen Resistance in Breast Cancer. Mol Cell Proteomics, 14(11):2887-900(2015) [pubmed]

curator keyword: Biomedical

submitter keyword: SILAC, FAK, estrogen receptor, tamoxifen

Akhilesh Pandey
contact affiliation	McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 USA
contact email	pandey@jhmi.edu
lab head
Muhammad Zahari
contact affiliation	Johns Hopkins School of Medicine
contact email	saddiq@jhmi.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD001812
     1. Label: PRIDE project
     2. Name: Phosphoproteomic analysis of tamoxifen resistant breast cancer