An Integrated Genomic Screen Identifies LDHB as an Essential Gene for Triple-Negative Breast Cancer

Abstract

Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ERþ/PRþ), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all three markers (triple negative or basal-like). While targeted therapies for ERþ/PRþ and HER2þ tumors have revolutionized patient treatment and increased lifespan, an urgent need exists for identifying novel targets for triple-negative breast cancers. Here, we used integrative genomic analysis to identify candidate oncogenes in triple-negative breast tumors and assess their function through loss of function screening. Using this approach, we identify lactate dehydrogenase B (LDHB), a component of glycolytic metabolism, as an essential gene in triple-negative breast cancer. Loss of LDHB abrogated cell proliferation in vitro and arrested tumor growth in fully formed tumors in vivo. We find that LDHB and other related glycolysis genes are specifically upregulated in basal-like/triplenegative breast cancers as compared with other subtypes, suggesting that these tumors are distinctly glycolytic. Consistent with this, triple-negative breast cancer cell lines were more dependent on glycolysis for growth than luminal cell lines. Finally, we find that patients with breast cancer and high LDHB expression in their tumors had a poor clinical outcome. While previous studies have focused on the ubiquitous role of LDHA in tumor metabolism and growth, our data reveal that LDHB is upregulated and required only in certain cancer genotypes. These findings suggest that targeting LDHB or other components of lactate metabolism would be of clinical benefit in triple-negative breast cancer. Cancer Res; 72(22); 5812-23. Ó2012 AACR.

ADHFE1 is a breast cancer oncogene and induces metabolic reprogramming

“…However, we did not find that L-2HG levels correlated with transcript expression of hypoxiainducible lactate dehydrogenase A in these tumors, an enzyme that has been linked to hypoxia-related L-2HG production (41). Instead, L-2HG strongly correlated with lactate dehydrogenase B mRNA levels (ρ = 0.93, P < 0.01), which is an enzyme critical for the development of triple-negative tumors (43).…”

Radiation-induced Gene Signature Predicts Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer Patients

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miR-200 promotes the mesenchymal to epithelial transition by suppressing multiple members of the Zeb2 and Snail1 transcriptional repressor complexes

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