Specific Molecular Signature Linked to Aggressive Triple-Negative Breast Cancers

Specific Molecular Signature Linked to Aggressive Triple-Negative Breast Cancers

Researchers at the Huntsman Cancer Institute, University of Utah and The Fourth Military Medical University, China, discovered the molecular mechanisms underlying the growth and survival of a specific type of aggressive breast cancer — triple-negative breast cancer. The study was published in the journal Proceedings of the National Academy of Sciences (PNAS) and is entitled “Metabolic reprogramming in triple-negative breast cancer through Myc suppression of TXNIP.

It is estimated that 15% of all diagnosed breast cancers correspond to triple-negative breast cancers, a type that lacks the receptors commonly targeted in chemotherapy — estrogen, progesterone and human epidermal growth factor receptor 2 (HER2). Compared to other breast cancer types, triple-negative breast cancers are usually more aggressive, non-responsive to targeted therapeutic drugs and patients frequently have a higher risk of recurrence and a shorter survival rate.

Triple-negative breast cancers are known to be highly glycolytic, meaning that they consume high amounts of the sugar glucose. “Normal cells do use glucose and glutamine,” explained the study’s senior author Dr. Donald Ayer in a news release, “but cancer cells use them at a very elevated rate and they actually become addicted to these nutrients and they are required for their growth.”

The research team discovered that two proteins named c-Myc and thirodoxin-interacting protein (TXNIP) are involved in the glucose metabolic phenotype observed. The proto-oncogene c-Myc usually stimulates glucose uptake in cancer cells to help them grow and survive, on the other hand, TXNIP is known to strongly block glucose uptake. In triple negative breast cancer cells, however, researchers found that c-Myc represses TXNIP expression, exacerbating c-Myc-driven glucose uptake and supporting cancer growth, suggesting that high levels of c-Myc and low levels of TXNIP promote cell growth and survival in triple negative breast cancer. In fact, high c-Myc levels and low TXNIP levels were found in patients with a poor clinical outcome. Interestingly, this interaction between c-MYC and TXNIP is only observed in aggressive triple negative breast cancers and not in other types of breast cancer, suggesting that it is linked to aggressive forms of the disease.

This finding may offer a new therapeutic target for triple-negative breast cancers. “From a therapeutic standpoint you could imagine that the cells that are addicted to these nutrients could be starved and killed more easily than normal cells,” noted Dr. Ayer.

The research team also found evidence suggesting that both c-Myc and TXNIP seem to have a role in cancer metastasis and the spread of cancer cells to other regions of the body. “What we discovered was that if tumors are taken from relatively young women, under age 53 with stage 1 or stage 2 breast cancers, and they have a high Myc, low TXNIP gene signature, these patients are more likely to have secondary metastasis later in life. We think this signature may be an early marker for metastatic disease,” concluded Dr. Ayer.

The research team believes that if their results are confirmed in human clinical trials, then the presence of a molecular signature with a high c-Myc expression and low TXNIP can identify women with breast cancer who are at a higher risk for recurrence and who could benefit from a more aggressive treatment and close monitoring.