Research Roundup: Mount Sinai Uncovers a Key to Breast Cancer Metastasis

Precancerous cells sometimes die out. Sometimes they begin to spread and grow, becoming malignant. Why isn’t it well understood? Mount Sinai researchers have discovered a key mechanism for how this occurs in breast cancer. For that and more research stories, continue reading.

How Early Breast Cancer Cells Get Switched on to Become Metastatic Breast Cancer

Researchers at Mount Sinai Hospital/Mount Sinai School of Medicine identified a previously unknown mechanism for how not-yet-malignant cells from early breast cancer tumors move to other organs and are stimulated into metastatic breast cancer. It is based on the ability of transcription factor NR2F1. This protein controls a gene’s outward expression that blocks pre-cancerous cells from metastasizing. They published their research in the journal Cancer Research.

“The current challenge for the management of treatment of early-stage breast cancer patients (for instance, patients who have non-invasive lesions such as ductal carcinoma in situ), is that even though local invasive recurrences are reduced after surgery or surgery with radiation, the risk of dying from breast cancer remains the same,” said Maria Soledad Sosa, Ph.D., assistant professor of pharmacological sciences, and oncological sciences, at The Tisch Cancer Institute at Mount Sinai, and lead author of the study. “This suggests that before detection and removal of the invasive tumor mass, some pre-malignant cells disseminated and lodged at other sites, waiting for later reactivation. The identification of an ‘early dissemination signature’ in the breast tissue that could identify patients at risk of developing later relapses, who are therefore candidates for systemic therapy, is crucial to reduce mortality in these patients.”

Using high-resolution intravital imaging of HER2+ early-stage cancer cells, the researchers found that loss of function of NR2F1 increased in vivo dissemination and was accompanied by decreased E-cadherin expression, activation of WNT-dependent beta-catenin signaling, disorganized laminin 5 deposition, and increased expression of EMT genes such as TWIST1, ZEB1, and PRRX1. Downregulation of NR2F1 also promoted a hybrid luminal/basal phenotype. In short, pre-malignant cells downregulated the levels of NR2F1. This helped these pre-malignant cells to disseminate along with upregulation of PRRX1, a master regulator of an invasive phenotype.

Mitochondrial Genome Editing

Researchers with the Center for Genome Engineering within the Institute for Basic Science created a new gene-editing platform dubbed transcription activator-like effector-linked deaminases (TALED). This system can perform A-to-G base conversion in mitochondrian, the organelles within the cell that generate energy. Although gene editing is generally successful in the nucleus of cells, up to now, editing the genome of mitochondria has been unsuccessful. Yet some very severe hereditary diseases come about from mutations in mitochondrial DNA, such as Leber hereditary optic neuropathy (LHON) and mitochondrial encephalomyopathy with lactic acidosis and stroke-related episodes (MELAS). There are also suggestions that mitochondrial DNA mutations may be linked to Alzheimer’s disease and muscular dystrophy. The mitochondrial genome is passed down from mothers. There are 90 known disease-causing point mutations in mitochondrial DNA.

GI Parasites Promote Health

The microbiome is the trillions of organisms — bacteria, viruses, fungi, etc. — that live in and on the body. And not all of them are harmful, as science is increasingly finding. Researchers at the National University of Singapore, Yong Loo Lin School of Medicine identified a common parasite in the GI tract of humans, Blastocystis subtype (ST) 4, which is associated with benefits for the gut. The parasite appears to suppress gut inflammation and behaves similar to probiotics in keeping the gut healthy. In laboratory models, they found the parasite stabilized the bacteria ecosystem in the gut and promoted faster recovery from inflammation. More research will be needed, but they theorize that Blastocystis STF increases the types of bacteria that produce beneficial molecules while increasing immune cells that tamp down inflammation. They say it behaves like an “ecosystem engineer.”

Controlling Blood Sugar May Improve Aerobic Capacity

It’s common knowledge that exercise can help control blood sugar, help save off pre-diabetes, type 2 diabetes, help control blood sugar levels in type 1 diabetes, and delay diabetes-related nerve damage and heart disease. But now researchers are looking at the reverse — can controlling blood glucose levels improve athletic performance? Researchers at the Joslin Diabetes Center note that high blood glucose impairs aerobic capacity. So, researchers at the center, part of Harvard Medical School, tested a drug called canagliflozin, which reduces blood glucose in a mouse model. They then evaluated the aerobic capacity of the animals on exercise wheels over a six-week study. They found that having high blood sugar for long periods changes the way muscles respond to exercise in the molecular model. And that by reducing blood glucose levels, at least in diabetic mice, using canagliflozin, prevents aerobic impairment. The next step is to test if other glucose-lowering treatments, such as diet, were also effective in improving exercise response.

Cancer as a Metabolic Disease?

Cancer is generally thought of as a genetic disease and/or an environmental disease. There is, however, a third approach, which is of cancer as a metabolic disease. Researchers at the University of Alberta are looking at the “metabolome.” They note that when using a genetic perspective, there are approximately 1,000 genes that, when mutated can cause cancer. Generally, it takes at least two different mutations for cancer to grow, leading to a million potential mutation pairs, which is a hugely complex level of science to unravel. However, in comparison, there are only four major metabolic types.

“Cancer is genetic, but often the mutation itself isn’t enough,” says David Wishart, professor in the U of A departments of biological sciences and computing science. As cancer develops and metastasizes, it creates its own environment and introduces specific metabolites. “It becomes a self-fueled disease. And that’s where cancer as a metabolic disorder becomes really important.”