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

Mark L Mccleland,Ron Firestein,Marie Evangelista,Eric Torres,Jiping Zha,Marcia Belvin,Elizabeth M Blackwood,Tom Truong,David Peterson,Laura Corson,Thomas Hunsaker,Benjamin Haley,Yonglei Shang,Li Li,Georgia Hatzivassiliou,Jean-Philippe Stephan,Adam S Adler

doi:10.1158/0008-5472.can-12-1098

Abstract

Breast cancer has been redefined into three clinically relevant subclasses: (i) estrogen/progesterone receptor positive (ER+/PR+), (ii) HER2/ERRB2 positive, and (iii) those lacking expression of all three markers (triple negative or basal-like). While targeted therapies for ER+/PR+ and HER2+ 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/triple-negative 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.

Highlights

In the past decade, molecular profiling has redefined breast cancer as a heterogeneous group of diseases
Of the 4 genes that met our significance criteria of scoring at a DZ-score (Z-score triple negative–Z-score luminal) of À0.9 or below, we found that only 1, lactate dehydrogenase B (LDHB), was required for proliferation of triplenegative breast cancers (Fig. 1C–E and Supplementary Fig. S1)
LDHB was selectively required for the growth of triple-negative breast cancers both in vitro and in vivo and was overexpressed in triple-negative breast

Summary

Introduction

Molecular profiling has redefined breast cancer as a heterogeneous group of diseases. The molecular distinction between these subtypes is defined by a tissue-specific gene signature and by the status of estrogen receptor (ER), progesterone receptor (PR), and ERBB2 (or HER2) In the clinic, these molecular subgroups translate into 3 major categories of breast cancer: (i) those that express ER or PR and are termed hormone receptor positive–dependent (HRþ), (ii) those with ERBB2/HER2 amplification (HER2þ), and (iii) those that lack expression of all 3 markers and are referred to as triple negative. These molecular subgroups translate into 3 major categories of breast cancer: (i) those that express ER or PR and are termed hormone receptor positive–dependent (HRþ), (ii) those with ERBB2/HER2 amplification (HER2þ), and (iii) those that lack expression of all 3 markers and are referred to as triple negative Authors' Affiliations: Departments of 1Pathology, 2Translational Oncology, 3Molecular Diagnostics & Cancer Cell Biology, 4Biochemical and Cellular Pharmacology, 5Bioinformatics & Computational Biology, and 6Protein Chemistry, Genentech, Inc., South San Francisco, California

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