Breast cancer cells can survive and proliferate under harsh conditions of nutrient deprivation, including limited
oxygen and
glucose availability. We hypothesized that such environments trigger metabolic adaptations of mitochondria, which promote
tumor progression. Here, we mimicked aglycemia and
hypoxia in vitro and compared the mitochondrial and cellular bioenergetic adaptations of human
breast cancer (HTB-126) and non-
cancer (HTB-125) cells that originate from breast tissue. Using high-resolution respirometry and western blot analyses, we demonstrated that 4 days of
glucose deprivation elevated oxidative phosphorylation five-fold, increased the spread of the mitochondrial network without changing its shape, and decreased the apparent affinity of
oxygen in
cancer cells (increase in C ( 50 )), whereas it remained unchanged in control cells. The substrate control ratios also remained constant following adaptation. We also observed the Crabtree effect, specifically in HTB-126 cells. Likewise, sustained
hypoxia (1%
oxygen during 6 days) improved cell respiration in non-
cancer cells grown in
glucose or
glucose-deprived medium (+ 32% and +38%, respectively). Conversely, under these conditions of limited
oxygen or a combination of
oxygen and
glucose deprivation for 6 days, routine respiration was strongly reduced in
cancer cells (-36% in
glucose medium, -24% in
glucose-deprived medium). The data demonstrate that
cancer cells behave differently than normal cells when adapting their bioenergetics to microenvironmental conditions. The differences in
hypoxia and aglycemia tolerance between
breast cancer cells and non-
cancer cells may be important when optimizing strategies for the treatment of
breast cancer.