c-Ski is an important corepressor of transforming

Many studies have identified metabolic pathways that underlie cellular transformation, but the metabolic drivers of cancer progression remain less well understood. The Hippo transducer pathway has been shown to confer malignant traits on breast cancer cells. In this study, we used metabolic mapping platforms to identify biochemical drivers of cellular transformation and malignant progression driven through RAS and the Hippo pathway in breast cancer, and identified platelet activating factor acetylhydrolase 1B3 (PAFAH1B3) as a key metabolic driver of breast cancer pathogenicity that is upregulated in primary human breast tumors and correlated with poor prognosis. Metabolomic profiling suggests that PAFAH1B3 inactivation attenuates cancer pathogenicity through enhancing tumor-suppressing signaling lipids. Our studies provide a map of altered metabolism that underlies breast cancer progression and put forth PAFAH1B3 as a critical metabolic node in breast cancer.

The erythroleukemia developed by spi-1/ PU.1-transgenic mice is a model of multistage oncogenic process. Isolation of tumor cells representing discrete stages of leukemic progression enables the dissection of some of the critical events required for malignant transformation. To elucidate the molecular mechanisms of multistage leukemogenesis, we developed a microarray transcriptome analysis of nontumorigenic (HS1) and tumorigenic (HS2) proerythroblasts from spi-1-transgenic mice. The data show that transcriptional up-regulation of the sphingosine kinase gene (SPHK1) is a recurrent event associated with the tumorigenic phenotype of these transgenic proerythroblasts. SPHK1 is an enzyme of the metabolism of sphingolipids, which are essential in several biologic processes, including cell proliferation and apoptosis. HS1 erythroleukemic cells engineered to overexpress the SPHK1 protein exhibited growth proliferative advantage, increased clonogenicity, and resistance to apoptosis in reduced serum level by a mechanism involving activation of the extracellular signal-related kinases 1/2 (ERK1/2) and phosphatidylinositol 3-kinase ( IntroductionThe acute erythroleukemia caused by the Friend virus is a multistage neoplasm suitable to study the sequence of oncogenic events involved in the progression of erythroblastic cells toward malignancy. 1 The early step of the Friend disease is characterized by a deregulation of growth and differentiation of erythropoietin (Epo)-independent erythroblasts. This phase is induced by the viral gp55 glycoprotein that constitutively activates the Epo receptor. 2 At a later stage, a clonal population of proerythroblasts emerges that are arrested in their differentiation and tumorigenic in vivo. 3,4 In these tumor cells, 2 recurrent genetic alterations have been identified: the transcriptional dysregulation of the spi-1 gene 5 (also called PU.1) and the extinction of the p53 gene. [6][7][8] Spi-1/PU.1 is a master gene in the development of B-lymphoid, monocyte, and neutrophilic lineages. [9][10][11] Ectopic overexpression of spi-1/PU.1 in proerythroblasts leads to cell transformation as demonstrated in vitro in avian erythroid progenitors infected by spi-1-transducing retroviruses 12 or in vivo in transgenic mice overexpressing spi-1 in hematopoietic cells. 13 Spi-1-transgenic mice develop an erythroleukemia arising from the proliferation of proerythroblasts arrested in their differentiation (HS1 stage). At disease onset, survival and growth of erythroblasts are under the control of Epo. Thus, the major effect of spi-1 overexpression in transgenic mice is a blockade in the differentiation of the erythroid lineage. Later during disease progression, malignant proerythroblasts characterized by Epo-autonomous growth and tumorigenicity in vivo can be isolated (HS2 stage). This multistep process suggested that genetic lesions were required to confer full malignancy. 13 Because of its recurrent alteration during Friend erythroleukemia, 1,7,8 mutation of the tumor suppressor gene p53 was a prime cand...