Abstract BS02-2: Alterations in tumor metabolism to support breast tumor growth and progression

Breast cancer cells must adapt metabolism to support anabolic processes and allow the accumulation of biomass to allow proliferation. However, tumor cells also experience periods of stress, and metabolic plasticity to shift metabolism to maximize efficiency and survive nutrient limitation is also needed for cancer progression. The M2 pyruvate kinase isoform (PKM2) is expressed in cancers and plays a role in regulating metabolism. To determine whether PKM2 is required for the development and growth of primary breast tumors, we generated mice harboring a conditional allele for PKM2. PKM2 deletion selectively abolishes PKM2 protein production while continued production of PKM1, the other major pyruvate kinase isoform. We crossed PKM2 conditional mice to a model of human breast cancer driven by loss of the Brca1 tumor suppressor gene. Contrary to prior expectation, mammary tumor formation and progression was accelerated despite PKM2 deletion. PKM2-null tumors displayed heterogeneous compensatory PKM1 expression, and expression of PKM1 was observed only in non-proliferating tumor cells. In contrast, proliferating cells in the tumor had no detectable pyruvate kinase expression. This suggests that PKM2 protein is not necessary for tumor cell proliferation and implies that the inactive state of PKM2 is associated with the proliferating cell population within tumors, while cells with active pyruvate kinase are involved in aspects of tumor progression that do not involve proliferation. Consistent with these findings, variable expression of PKM2 was observed across a panel of human breast tumors, and recurrent mutations resulting in disruption of one PKM2 allele are found in multiple human cancers. Together, these data support a model where regulation of PKM2 activity allows the enzyme to support the differential metabolic requirements of both proliferating and non-proliferating tumor cells. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr BS02-2.