6 months ago
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A previously unknown mechanism for inactivating genes that suppresses tumor formation helps explain why cancer risk is associated with an unhealthy diet or unmanaged metabolic conditions like diabetes.
Researchers from Singapore and the UK used mouse models, human tissue, and human breast organoids grown in the lab to find that changes in glucose metabolism could help cancer grow by temporarily disabling a gene that protects us from tumors called BRCA2.
"These findings raise awareness of the impact of diet and weight control in the management of cancer risks," says the first author of the new study, cancer pharmacologist Li Ren Kong from the Cancer Science Institute of Singapore (CSI Singapore).
"We started the study aiming to understand what factors elevate risk in families susceptible to cancer, but ended up discovering a deeper mechanism linking an essential energy consumption pathway to cancer development."
The discovery also challenges a long-established theory about genes that protect against cancer. Knudson's 'two-hit' paradigm, first proposed in 1971, states that both copies of a tumor suppressor gene must be permanently inactivated in our cells before cancer can start.
Recent studies found that a mutation in one of a cell's two BRCA2 genes is implicated in various cancers. Interestingly, mice and human cells with this mutation don't show the usual signs of genetic instability seen in cells with both copies of the gene mutated.
In mice, having just one copy of BRCA2 affected doesn't seem to cause major issues in organ development or DNA repair in most tissues. But cells with this mutation appear more vulnerable to stresses, like exposure to environmental toxins such as formaldehyde or acetaldehyde, which can reduce their levels of BRCA2 protein, leading to functional problems.
"How such environmental factors increase cancer risk is not yet very clear, but it is vital to understand the connection if we are to take preventive measures that help us stay healthy longer," says oncologist and cancer researcher Ashok Venkitaraman from CSI Singapore.
The team first examined people who inherited one faulty copy of BRCA2. They found that cells from these people were more sensitive to methylglyoxal (MGO), which is produced when cells break down glucose for energy in the process of glycolysis.
Glycolysis generates over 90 percent of the MGO in cells, which a pair of enzymes typically keep to minimal levels. In the event they can't keep up, high MGO levels can lead to the formation of harmful compounds that damage DNA and proteins. In conditions like diabetes, where MGO levels are elevated due to high blood sugar, these harmful compounds contribute to disease complications.
The researchers discovered that MGO can temporarily disable the tumor-suppressing functions of the BRCA2 protein, resulting in mutations linked to cancer development. This effect could be seen in noncancerous cells as well as patient-derived tissue samples, in some cases of human breast cancer, and in mouse models of pancreatic cancer.
As the BRCA2 allele isn't permanently inactivated, functional forms of the protein it produces can later return to normal levels. But cells repeatedly exposed to MGO may continue to accumulate cancer-causing mutations whenever existing BRCA2 protein production fails.
Overall, this suggests that changes in glucose metabolism can disrupt BRCA2 function via MGO, contributing to the development and progression of cancer.
These results come from lab tests and small human tissue sample sizes, and the researchers say more studies need to be done using larger clinical studies or animal models to look into possible links between dietary factors, diabetes, and other metabolic disorders.
As MGO can temporarily rob the BRCA2 protein of its ability to repair DNA, it makes sense that a poor diet or uncontrolled diabetes could contribute to a higher risk of cancer over time, even in people with two functional copies of the BRCA2 gene. This new information may lead to strategies for cancer prevention or early detection.
"Methylglyoxal can be easily detected by a blood test for HbA1C, which could potentially be used as a marker," Venkitaraman says.
"Furthermore, high methylglyoxal levels can usually be controlled with medicines and a good diet, creating avenues for proactive measures against the initiation of cancer."
The research has been published in Cell.
