title: 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 (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.
authors.affiliation: Departments of Pathology, Genentech, Inc, South San Francisco, California 94080, USA.
authors.forename: Mark L
authors.initials: ML
authors.lastname: McCleland
authors.forename: Adam S
authors.initials: AS
authors.lastname: Adler
authors.forename: Yonglei
authors.initials: Y
authors.lastname: Shang
authors.forename: Thomas
authors.initials: T
authors.lastname: Hunsaker
authors.forename: Tom
authors.initials: T
authors.lastname: Truong
authors.forename: David
authors.initials: D
authors.lastname: Peterson
authors.forename: Eric
authors.initials: E
authors.lastname: Torres
authors.forename: Li
authors.initials: L
authors.lastname: Li
authors.forename: Benjamin
authors.initials: B
authors.lastname: Haley
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Stephan
authors.forename: Marcia
authors.initials: M
authors.lastname: Belvin
authors.forename: Georgia
authors.initials: G
authors.lastname: Hatzivassiliou
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Blackwood
authors.forename: Laura
authors.initials: L
authors.lastname: Corson
authors.forename: Marie
authors.initials: M
authors.lastname: Evangelista
authors.forename: Jiping
authors.initials: J
authors.lastname: Zha
authors.forename: Ron
authors.initials: R
authors.lastname: Firestein
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D048708:Cell Growth Processes / Q000235:genetics; D045744:Cell Line, Tumor; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D045022:Lactate Dehydrogenases / Q000096:biosynthesis / Q000235:genetics*; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D045022:Lactate Dehydrogenases; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; C071195:D-lactate dehydrogenase