If you took biology class in high school, you likely learned about mitochondria. Nestled inside our cells, these organelles are often depicted in textbooks as kidney bean-shaped structures floating outside the nucleus. Mitochondria’s main role is to produce the energy our cells need to function. But, a new study from the University of Chicago Medicine Comprehensive Cancer Center has found that mitochondrial health plays a large part in breast cancer growth and progression too.
Kay Macleod, PhD, associate professor in the Ben May Department for Cancer Research, and a team that included Gregory Karczmar, PhD, professor of radiology, have discovered that when mitochondria become dysfunctional, breast cancer is more likely to metastasize, or spread to other areas of the body. Their paper on the topic was published in the journal EMBO Reports in September.
The process by which cellular content is turned over is known as autophagy, which Macleod said plays a housekeeping role. “You can make the analogy of autophagy as the garbage collector that gets rid of all the junk in the cell,” she said. “But, then, the other important function is that the breakdown products get recycled.” During autophagy, damaged organelles, proteins and pathogens are recycled into materials the cell can use for growth, like amino acids.
A specific type of autophagy is mitophagy, the process by which damaged mitochondria are degraded and removed from the cell. Macleod and her colleagues used mouse models to study mitophagy in mammary (breast) tumor cells. The researchers discovered that a protein, called BNIP3, plays an important role in mitophagy. In fact, when the BNIP3 protein is missing in tumor cells, rates of mitophagy are markedly reduced.
“When BNIP3 is not there, mitochondria are not getting efficiently turned over,” Macleod says. “And, as a result of that, you get an accumulation of these unhealthy mitochondria that generate increased levels of reactive oxygen species.”
Reactive oxygen species (ROS) are highly reactive molecules that can harm cells by mutating DNA and damaging proteins and lipids, for example. ROS also play important signaling roles in cells, including induction of a transcription factor (protein that binds to DNA and controls gene expression) called hypoxia-inducible factor 1-alpha or HIF1A. HIF1A then causes metabolic changes and blood vessel growth that feed tumors and promote metastasis.
In essence, loss of BNIP3 starts a domino effect. BNIP3 loss halts mitophagy, ROS starts to build up, which induces HIF1A and ultimately speeds up metastasis. Macleod and her team found that reintroducing BNIP3 into cells stopped this chain reaction and slowed tumor growth.
They also found that loss of BNIP3 expression is prevalent in patients with triple-negative breast cancer, an aggressive type of breast cancer in which the tumor lacks three receptors to which several treatments are targeted. By mining data in The Cancer Genome Atlas, Macleod and her team found that triple-negative patients whose tumors express both high levels of HIF1A and low levels of BNIP3 experienced poor outcomes compared to those with high levels of HIF1A and normal levels of BNIP3.
“If you look at different subtypes of breast cancer and you look at the mitochondrial mass, it’s clear that different types of breast cancer have got very different levels of mitochondria. We really don’t understand why that is,” she said.
In on-going studies, Macleod and her team are investigating the significance of changes in mitochondrial mass for tumor treatment responses and in order to predict which tumors are likely to progress to metastasis.
“From our perspective, we’re really excited that people are starting to focus more on the role of mitochondria in cancer,” Macleod said. “Relatively speaking, the role mitochondria play in cancer is understudied.”
By studying the molecular networks that control how mitochondria function, it may be possible to design therapeutic treatments that repair mitochondrial defects in tumor cells. As this study shows, without regular housekeeping our cells can become just as disorganized as our homes.