A three-dimensional culture of human breast cancer cells. Source: National Cancer Institute
The most intractable common form of breast cancer might in most cases be treatable by drugs that target fat metabolism, according to UC San Francisco researchers who discovered the tumors’ frequent dependence on fat as an energy source, and then successfully treated human breast tumors that they transplanted and grew in mice.
Roughly one-in-five invasive breast cancers are categorized as triple negative, meaning they do not rely on the hormones estrogen and progesterone for growth, nor on human epidermal growth factor receptor 2 (HER2). Given this, they are not vulnerable to modern hormonal therapies or to the HER2-targeted drug Herceptin (trastuzumab). Because they grow rapidly in early stages, triple-negative breast tumors often respond well initially to older chemotherapies that kill dividing cells, but a greater percentage of women diagnosed with this type of breast cancer die within five years of diagnosis because of the emergence of cancer metastasis.
In a new study published online on March 7 in Nature Medicine, researchers led by breast oncologist Andrei Goga, MD, PhD, a professor of cell and tissue biology and of medicine, and a member of the Helen Diller Family Comprehensive Cancer Center at UCSF, showed that overexpression of a cancer gene called MYC (pronounced “mick”) in triple-negative breast cancer appears to drive tumors toward a dependency on fat metabolism to satisfy their appetite for a growth-fueling source of energy. The researchers succeeded in halting tumor growth with a drug, etomoxir, that targets fat oxidation. Etomoxir was originally developed to treat heart failure.
Goga previously led a study in which researchers determined that about 9 out of ten triple-negative breast cancers make excessive amounts of a protein encoded by the MYC gene, a well-known “oncogene” that drives the development of many tumor types. However, pharmaceutical companies have not been able to successfully target MYC despite decades of trying.
While early cancer-fighting strategies focused on rapid cell division in tumors, more recently scientists have increasingly been studying tumors’ abnormal metabolism. Goga and others previously discovered that MYC affects metabolic pathways as cancers develop.
Researchers have focused attention on abnormally high rates of glucose metabolism in tumors, first discovered nearly a century ago. However, for the new Nature Medicine study the scientists used a technique called mass spectrometry to identify metabolites associated with triple-negative breast tumors that arose in mice when MYC expression was abnormally elevated. In collaboration with the research group of Daniel K. Nomura, PhD, associate professor of chemistry and of nutritional sciences and toxicology at UC Berkeley, they found an unusual abundance of fatty acid oxidation metabolites, indicating that triple-negative breast cancer cells may be oxidizing fat to satisfy their energy needs.
In addition to studying these transgenic mice that had a switchable MYC gene, the researchers worked with human tumor tissue, with clinical data from The Cancer Genome Atlas (TCGA) and other public databases, and with tumor cells growing in the lab. UCSF graduate student Roman Camarda designed and conducted most of the experiments and wrote up the study for publication.
In triple-negative breast cancer cells with increased MYC activity grown in the lab, etomoxir inhibited production of the molecule ATP, the common energy currency of cells, but did not have the same effect on other types of breast cancer cells.
In an analysis of TCGA data from 771 breast cancer patients, the researchers found that 244 genes associated with fatty acid metabolism were expressed abnormally in triple-negative breast cancers, and they determined from their database analysis that abnormally controlled fatty acid oxidation is likely important for the sustenance of triple-negative breast cancers in humans.
From patient data, the researchers also determined that low levels of activation of the gene that makes the ACC2 enzyme, which normally restricts fatty acid oxidation, was associated with worse survival in breast cancer patients, especially those with triple-negative breast cancer.