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Expression data from MCF7 Scrambled and SIM2si cells

ABSTRACT: MCF7 breast cancer cells are a luminal-type breast cancer with moderate native levels of SIM2s. To determine effects of SIM2s on tumor progression, cells were stably transduced with SIM2si shRNA to knockdown expression, inducing an EMT effect. Microarray analysis was performed to determine genetic pathways involved in this phenotype. The coordination of cellular metabolism is a key factor in the progression of ductal carcinoma in situ (DCIS) to invasive ductal carcinoma (IDC). Pathways regulating the balance between oxidative phosphorylation and glycolysis are unclear. We have found that transcription factor Singleminded-2s (SIM2s), commonly lost with breast cancer progression, contributes to metabolic regulation by controlling glycolytic flux and cellular senescence. Through promotion of p21 and cellular senescence, SIM2s decreases glycolytic enzyme activity and promotes oxidative phosphorylation in breast cancer. These, coupled with increased autophagy and ROS, inhibit tumor growth and metastasis. We use microarrays to detail the global gene programming changes that occur with loss of SIM2s gene expression.

ORGANISM(S): Homo sapiens

PROVIDER: GSE44187 | GEO | 2013/02/08

SECONDARY ACCESSION(S): PRJNA189047

REPOSITORIES: GEO

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Project description:Many cancers rely on glycolytic metabolism to fuel rapid proliferation. This has spurred interest in designing drugs that target tumor glycolysis such as AZD3965, a small molecule inhibitor of Monocarboxylate Transporter 1 (MCT1) currently undergoing Phase I evaluation for cancer treatment. Since MCT1 mediates proton-linked transport of monocarboxylates such as lactate and pyruvate across the plasma membrane (Halestrap and Meredith, 2004), AZD3965 is thought to block tumor growth through disruption of lactate transport and glycolysis. Here we show that MCT1 inhibition impairs proliferation of glycolytic breast cancer cells that express MCT4 via disruption of pyruvate rather than lactate export. We found that MCT1 expression is elevated in glycolytic breast tumors and cell lines as well as in malignant breast and lung tissues. High MCT1 expression predicts poor prognosis in breast and lung cancer patients. Stable knockdown and AZD3965-mediated inhibition of MCT1 promote oxidative metabolism. Acute inhibition of MCT1 reduces pyruvate export rate but does not consistently alter lactate transport or glycolytic flux in breast cancer cells that also express MCT4. Despite the lack of glycolysis impairment, MCT1 loss-of-function decreases breast cancer cell proliferation and blocks growth of mammary fat pad xenograft tumors. Our data suggest that MCT1 expression is elevated in glycolytic cancers to promote pyruvate export, which when inhibited enhances oxidative metabolism and reduces proliferation. This study presents an alternative molecular consequence of MCT1 inhibitors that further supports their use as anti-cancer therapeutics. Since MCT1 levels are elevated in glycolytic and malignant breast tumors, we hypothesized that MCT1 may contribute to the Warburg effect metabolic phenotype. To test this hypothesis, we generated whole genome microarray data from breast cancer cell lines either a) expressing a short hairpin (sh)RNA-mediated stable knockdown of MCT1; or b) treated for 24 hours with an MCT1 inhibitor (AZD3965). Scramble shRNA or DMSO were used as controls, and all conditions were analzed in triplicate. The cell lines used â HS578T, SUM149PT, and SUM159PT â are among the most glycolytic in a panel of 31 breast cancer cell lines.

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Expression data from MCF7 Scrambled and SIM2si cells

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