Amplification and over expression of erbB2/neu proto-oncogene is observed in 20–30% human breast cancer and is inversely correlated with the survival of the patient. Despite this, somatic activating mutations within erbB2 in human breast cancers are rare. However, we have previously reported that a splice isoform of erbB2, containing an in-frame deletion of exon 16 (herein referred to as ErbB2ΔEx16), results in oncogenic activation of erbB2 due to constitutive dimerization of the ErbB2 receptor. Here, we demonstrate that the ErbB2ΔEx16 is a major oncogenic driver in breast cancer that constitutively signals from the cell surface. We further show that inducible expression of the ErbB2Ex16 variant in mammary gland of transgenic mice results in the rapid development of metastatic multifocal mammary tumors. Genetic and biochemical characterization of the ErbB2ΔEx16 derived mammary tumors exhibit several unique features that distinguish it from the conventional ErbB2 models expressing the erbB2 proto-oncogene in mammary epithelium. Unlike the wild-type ErbB2 derived tumors that express luminal keratins, ErbB2ΔEx16 derived tumors exhibit high degree of intra-tumoral heterogeneity co-expressing both basal and luminal keratins. Consistent with these distinct pathological features, the ErbB2ΔEx16 tumors exhibited distinct signaling and gene expression profiles that correlated with activation of number of key transcription factors implicated in breast cancer metastasis and cancer stem cell renewal.

Tumor cells utilize glucose as a primary energy source and require ongoing lipid biosynthesis for growth. Expression of DecR1, an auxiliary enzyme in the fatty acid ␤-oxidation pathway, is significantly diminished in numerous spontaneous mammary tumor models and in primary human breast cancer. Moreover, ectopic expression of DecR1 in ErbB2/Neu-induced mammary tumor cells is sufficient to reduce levels of ErbB2/Neu expression and impair mammary tumor outgrowth. This correlates with a decreased proliferative index and reduced rates of de novo fatty acid synthesis in DecR1-expressing breast cancer cells. Although DecR1 expression does not affect glucose uptake in ErbB2/Neu-transformed cells, sustained expression of DecR1 protects mammary tumor cells from apoptotic cell death following glucose withdrawal. Moreover, expression of catalytically impaired DecR1 mutants in Neu-transformed breast cancer cells restored Neu expression levels and increased mammary tumorigenesis in vivo. These results argue that DecR1 is sufficient to limit breast cancer cell proliferation through its ability to limit the extent of oncogene expression and reduce steady-state levels of de novo fatty acid synthesis. Furthermore, DecR1-mediated suppression of tumorigenesis can be uncoupled from its effects on Neu expression. Thus, while downregulation of Neu expression may contribute to DecR1-mediated tumor suppression in certain cell types, this is not an obligate event in all Neu-transformed breast cancer cells.

Rab Coupling Protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10-25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triple negative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the patho-biological role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model co-expressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context ErbB2-positive breast cancer, and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression.

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