We recently reported that loss of one or both alleles of Ralbp1, which encodes the stress-protective
protein RLIP76 (Rlip), exerts a strong dominant negative effect on both the inherent
cancer susceptibility and the chemically inducible
cancer susceptibility of mice lacking one or both alleles of the
tumor suppressor p53. In this paper, we examined whether congenital Rlip deficiency could prevent genetically-driven
breast cancer in two transgenic mouse models: the MMTV-PyVT model, which expresses the polyomavirus middle
T antigen (PyVT) under control of the mouse mammary tumor virus promoter (MMTV) and the MMTV-Erbb2 model which expresses MMTV-driven erythroblastic
leukemia viral oncogene homolog 2 (Erbb2, HER2/Neu) and frequently acquires p53 mutations. We found that loss of either one or two Rlip alleles had a suppressive effect on
carcinogenesis in Erbb2 over-expressing mice. Interestingly, Rlip deficiency did not affect
tumor growth but significantly reduced the lung metastatic burden of
breast cancer in the viral PyVT model, which does not depend on either Ras or loss of p53. Furthermore, spontaneous
tumors of MMTV-PyVT/Rlip+/+ mice showed no regression following Rlip knockdown. Finally, mice lacking one or both Rlip alleles differentially expressed markers for apoptotic signaling, proliferation, angiogenesis, and cell cycling in PyVT and Erbb2
breast tumors. Our results support the efficacy of Rlip depletion in suppressing p53 inactivated
cancers, and our findings may yield novel methods for prevention or treatment of
cancer in patients with HER2 mutations or
tumor HER2 expression.