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.
journal_name
Cancer Resjournal_title
Cancer researchauthors
McCleland ML,Adler AS,Shang Y,Hunsaker T,Truong T,Peterson D,Torres E,Li L,Haley B,Stephan JP,Belvin M,Hatzivassiliou G,Blackwood EM,Corson L,Evangelista M,Zha J,Firestein Rdoi
10.1158/0008-5472.CAN-12-1098subject
Has Abstractpub_date
2012-11-15 00:00:00pages
5812-23issue
22eissn
0008-5472issn
1538-7445pii
0008-5472.CAN-12-1098journal_volume
72pub_type
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