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.Electronic supplementary materialThe online version of this article (doi:10.1186/2193-1801-2-497) contains supplementary material, which is available to authorized users.
Highlights
Inflammatory breast cancer (IBC) is the most metastatic form of breast cancer (Robertson et al 2010)
anaplastic lymphoma kinase (ALK) in IBC patient tumors A set of 25 randomly selected IBC patient tumors were analyzed using the Food and drug administration (FDA) approved fluorescence in situ hybridization (FISH) detection method based on the Vysis ALK Break Apart Probe for detection of Echinoderm microtubule associated protein-like 4 (EML4)-ALK translocation and gene amplification (Shaw et al 2011)
As an example of the interpretation of FISH analysis for one IBC sample reflective of the heterogeneity of ALK copy number alterations or ALK amplification detected in IBC patients, the report was “negative for rearrangements involving the ALK gene, with three to four copies of ALK observed in 59.0% of cells, five to six copies of ALK observed in 11.0% of cells and seven to eight copies of ALK were observed in 6.0% of cells, suggesting the presence of a neoplasm with gains of chromosome 2 or 2p”
Summary
Inflammatory breast cancer (IBC) is the most metastatic form of breast cancer (Robertson et al 2010). Inflammatory breast cancer (IBC) has been defined as a clinical-pathologic entity characterized by diffuse erythema and edema (peau d’orange) involving a third or more of the skin of the breast (American Joint Committee on Cancer Staging Manual 2010). The average survival of IBC patients (2.9 years) is significantly less than the survival rate of patients diagnosed with non-IBC locally advanced breast cancer (6.4 years) and the >10-year survival rate of patients with non-T4 (i.e., non-locally advanced) breast cancer (Hance et al 2005). A few genes, such as Rho C GTPase, have been associated with the invasive phenotype of IBC (Van Golen et al 2000; Kleer et al 2005) and the underlying genetic changes in IBC remain largely undefined. The lack of the understanding of the molecular underpinnings of IBC points out the critical need to identify abnormalities in gene and protein signaling pathways that are activated in IBC in order to provide new therapeutic strategies to IBC patients who are routinely excluded from clinical trials
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
