Women with HER2(+) or triple negative/basal-like (TN/BL) breast
cancers succumb to their
cancer rapidly due, in part to acquired
Herceptin resistance and lack of TN/BL-targeted
therapies. BRCA1-IRIS is a recently discovered, 1399 residue, BRCA1 locus alternative product, which while sharing 1365 residues with the full-length product of this tumor suppressor gene, BRCA1/p220, it has
oncoprotein-like properties. Here, we examine whether BRCA1-IRIS is a valuable treatment target for HER2(+) and/or TN/BL
tumors.
METHODOLOGY/PRINCIPAL FINDINGS: Immunohistochemical staining of large cohort of human
breast tumor samples using new monoclonal anti-BRCA1-IRIS antibody, followed by correlation of BRCA1-IRIS expression with that of AKT1, AKT2, p-AKT,
survivin and BRCA1/p220,
tumor status and age at diagnosis. Generation of subcutaneous
tumors in SCID mice using human mammary epithelial (HME) cells overexpressing TERT/LT/BRCA1-IRIS, followed by comparing AKT,
survivin, and BRCA1/p220 expression,
tumor status and aggressiveness in these
tumors to that in
tumors developed using TERT/LT/Ras(V12)-overexpressing HME cells. Induction of primary and invasive rat mammary
tumors using the
carcinogen N-methyl-N-nitrosourea (NMU), followed by analysis of rat BRCA1-IRIS and ERα
mRNA levels in these
tumors. High BRCA1-IRIS expression was detected in the majority of human
breast tumors analyzed, which was positively correlated with that of AKT1-, AKT2-, p-AKT-,
survivin, but negatively with BRCA1/p220 expression. BRCA1-IRIS-positivity induced high-grade, early onset and metastatic HER2(+) or TN/BL
tumors. TERT/LT/BRCA1-IRIS overexpressing HME cells formed invasive subcutaneous
tumors that express high AKT1, AKT2, p-AKT and
vimentin, but no CK19, p63 or BRCA1/p220. NMU-induced primary and invasive rat breast
cancers expressed high levels of rat BRCA1-IRIS
mRNA but low levels of rat ERα
mRNA.
CONCLUSION/SIGNIFICANCE: