Title: Presence of anaplastic lymphoma kinase in inflammatory breast cancer
Authors: Robertson, Fredika M ×
Petricoin Iii, Emanuel F
Van Laere, Steven
Bertucci, Francois
Chu, Khoi
Fernandez, Sandra V
Mu, Zhaomei
Alpaugh, Katherine
Pei, Jianming
Circo, Rita
Wulfkuhle, Julia
Ye, Zaiming
Boley, Kimberly M
Liu, Hui
Moraes, Ricardo
Zhang, Xuejun
Demaria, Ruggero
Barsky, Sanford H
Sun, Guoxian
Cristofanilli, Massimo #
Issue Date: 2013
Publisher: SpringerOpen
Series Title: SpringerPlus vol:2 pages:497
Article number: 10.1186/2193-1801-2-497
Abstract: Although Inflammatory Breast Cancer (IBC) is recognized as the most metastatic variant of locally advanced breast cancer, the molecular basis for the distinct clinical presentation and accelerated program of metastasis of IBC is unknown. Reverse phase protein arrays revealed activation of the receptor tyrosine kinase, anaplastic lymphoma kinase (ALK) and biochemically-linked downstream signaling molecules including JAK1/STAT3, AKT, mTor, PDK1, and AMPKβ in pre-clinical models of IBC. To evaluate the clinical relevance of ALK in IBC, analysis of 25 IBC patient tumors using the FDA approved diagnostic test for ALK genetic abnormalities was performed. These studies revealed that 20/25 (80%) had either increased ALK copy number, low level ALK gene amplification, or ALK gene expression, with a prevalence of ALK alterations in basal-like IBC. One of 25 patients was identified as having an EML4-ALK translocation. The generality of gains in ALK copy number in basal-like breast tumors with IBC characteristics was demonstrated by analysis of 479 breast tumors using the TGCA data-base and our newly developed 79 IBC-like gene signature. The small molecule dual tyrosine kinase cMET/ALK inhibitor, Crizotinib (PF-02341066/Xalkori®, Pfizer Inc), induced both cytotoxicity (IC50 = 0.89 μM) and apoptosis, with abrogation of pALK signaling in IBC tumor cells and in FC-IBC01 tumor xenograft model, a new IBC model derived from pleural effusion cells isolated from an ALK(+) IBC patient. Based on these studies, IBC patients are currently being evaluated for the presence of ALK genetic abnormalities and when eligible, are being enrolled into clinical trials evaluating ALK targeted therapeutics.
ISSN: 2193-1801
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Gynaecological Oncology
× corresponding author
# (joint) last author

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