Of all of the breast cancer cell lines developed in my lab, none have been more widely used than the SUM-149 cell line. There are several reasons for this. One is that this cell line is an excellent example of a basal breast cancer cell line, or a BL2 breast cancer cell line, with overexpression and constitutive activation of the epidermal growth factor receptor (EGFR). For this reason, SUM-149 has been of special interest to my lab for many years. A second reason is that this cell line is one of two lines (the other being SUM-190) that was derived from a patient with inflammatory breast cancer. Thus, any lab anywhere who works on or has an interest in inflammatory breast cancer works with these cells. Given the fact that SUM-149 was derived from an aggressive breast cancer that occurred in an African American patient also makes this line a good model of the kind of aggressive disease that is all too common in African Americans. Finally, this cell line has a BRCA1 mutation, and is thus one of only a handful of breast cancer cell lines with this genomic alteration.
From the perspective of the Ethier lab, we have been interested in SUM-149 cells ever since we discovered that the primary mechanism for the overexpression at the protein level of EGFR and it’s constitutive activation is the synthesis and secretion of the EGF-family ligand Amphiregulin (AREG). We have published many papers on the AREG-EGFR interaction demonstrating its importance not only for driving cell proliferation via EGFR activation, but also motility and invasion, and the activation of inflammatory pathways involving NFkB and IL1. AREG actually stabilizes EGFR protein resulting in overexpression and membrane localization, two features that we equate with oncogenic signaling. Thus, AREG activated EGFR behaves much like EGFR in the context of gene amplification.
We’ve learned recently that SUM-149 cells belong to a group of breast cancers that do not have activated oncogenes in the classical sense. Rather, they belong to a class of triple negative breast cancers that exhibit a particular type of genomic instability called the Tandem Duplicator Phenotype. This type of genomic instability is the result of TP53 mutations in the context of either BRCA1 mutations or BRCA1 loss of function, and one result of this phenotype is the disruption of a number of tumor suppressor genes, particularly PTEN. Indeed, the PTEN gene is disrupted in these cells, resulting in loss of message and protein expression without changes in the coding sequence. The loss of PTEN in these cells results in constitutive activation of the PI3’K/AKT pathway, and indeed in these cells, both AKT1 and AKT3 are constitutively activated. We believe the activation of two AKT isoforms explains the lack of AKT being a hit in our shRNA screen, as loss of one AKT isoform is compensated by the other isoform. Despite the fact that there is constitutive PI3’K/AKT activity in these cells, the mTOR pathway is exceptionally quiet, both at the level of the shRNA screen, and at the level of the reverse phase protein array analysis performed with these cells, which showed under-expression of many of the proteins in this pathway. These results explain the resistance of these cells to mTOR inhibitors such as rapamycin and everolimus.
The bibliography contains references to the work in the literature making use of SUM-149 as a model for inflammatory breast cancer.
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