Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks the three common receptors found in other types of breast cancer: estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). This absence of receptors limits the effectiveness of traditional hormone therapies, making TNBC a recalcitrant disease with a poorer prognosis. Recent research has explored the potential of dietary interventions, specifically low methionine diets, in combination with other therapies to improve outcomes for TNBC patients.
Understanding Triple-Negative Breast Cancer (TNBC)
TNBC is characterized by its high malignancy and poor prognosis. A notable feature of TNBC is the high frequency of BRCA1 gene mutations, which inhibit homologous-recombination DNA repair (HR), making it difficult for cells to repair DNA double-strand breaks (DSBs).
The Role of Methionine in Cancer
Methionine is an essential amino acid crucial for various cellular processes, including cell metabolism, DNA repair, and antioxidant protection. Cancer cells, due to their rapid growth and division, have a higher demand for methionine compared to normal cells. This increased need creates a vulnerability that researchers are exploring as a potential therapeutic target.
Cancer cells produce normal or greater-than-normal amounts of methionine from homocysteine but require exogenous methionine to survive, which is termed methionine addiction or the Hoffman effect. Normal cells do not require exogenous methionine for survival when grown on homocysteine. Methionine addiction is thought to be caused by an increased methionine requirement in cancer cells due to excessive transmethylation reactions.
Methionine Restriction: A Potential Therapeutic Strategy
Methionine restriction (MR) involves reducing the availability of methionine in the diet. Laboratory research suggests that MR can make cancer cells more vulnerable to DNA-damaging therapies like chemotherapy and radiation therapy, enhancing their response to these treatments.
Read also: The Science of Low Methionine Diets
How Methionine Restriction Affects Cancer Cells
MR causes cancer cells to arrest in the S/G2 phase of the cell cycle and induces apoptosis (programmed cell death). Many chemotherapeutic agents targeting the S/G2 phase of the cell cycle have synergistic efficacy against cancer cells when combined with MR. In contrast, normal mammalian cells proliferate under MR.
Recombinant Methioninase (rMETase)
Recombinant methioninase (rMETase) is an enzyme that degrades extracellular methionine, targeting the methionine addiction of cancer. Previous studies have demonstrated the efficacy of rMETase in preclinical models and patients with breast cancer.
Research on Low Methionine Diets and TNBC
Several studies have investigated the effects of methionine restriction on TNBC cells, both alone and in combination with other therapies.
Synergistic Effects with PARP Inhibitors
One study examined the efficacy of methionine restriction and the poly ADP-ribose polymerase (PARP)-inhibitor olaparib on BRCA1/2 wild-type and BRCA1 mutated TNBC cell lines. The results showed that methionine restriction and olaparib had synergistic efficacy on the BRCA1-mutant TNBC cell line HCC1937. The BRCA1-mutant cell line MDA-MB-436 was most sensitive to rMETase. The BRCA1/2 wild-type TNBC cell line MDA-MB-231 was sensitive to a methionine-free medium but resistant to olaparib. Therefore, methionine restriction has clinical potential for BRCA1/2 wild-type and BRCA1-mutant olaparib-resistant and -sensitive TNBC.
The PARP inhibitor olaparib is a molecular-targeted drug that inhibits tumors with homologous-recombination deficiency and is used for breast-cancer patients with BRCA1/2 mutations. However, sensitivity to PARP inhibitors varies among cells and patients with BRCA1/2 mutations, and resistance to PARP inhibitors have become a recalcitrant clinical problem. Thus, it is critical to overcome resistance to PARP inhibitors.
Read also: Risks of Methionine Restriction
Mouse Model Studies
Researchers at the University of Wisconsin fed mice with triple-negative breast tumors a diet lacking methionine and treated them with an antibody that binds to the TRAIL-R2 receptor. The study found that removing methionine can have a specific effect on a molecular pathway that regulates cell death, increasing the vulnerability of cancer cells to treatments that target this pathway. Interestingly, normal, non-cancer cells did not upregulate the receptor under methionine stress the way the tumor cells did.
Clinical Trial Potential
The University of Wisconsin team believes that their laboratory studies may pave the way for a clinical trial in breast cancer patients to examine the effectiveness of a low-methionine diet in combination with a TRAIL-R2 monoclonal antibody. The hope is that brief exposure to a low methionine diet will boost the effectiveness of TRAIL-R2 antibodies in patients, as it did in mice.
Considerations for Implementing a Low Methionine Diet
Implementing a methionine-restricted diet requires careful attention to ensure that nutritional needs are still met. A substantially reducing methionine consumption requires a diet that is either vegan or with very limited amounts of dairy products and eggs. A plants-only diet can be nutritionally adequate when properly planned, although there’s an added challenge to meet increased protein needs during cancer treatment.
Lower Methionine, Not No Methionine
In cell studies, it’s possible to create conditions with no methionine present at all. Methionine reduction studies in animals typically reduce dietary methionine to cut circulating levels to about half of usual levels, ensuring that physiological needs are still met.
Reducing Methionine, Not Protein or Calories
In mice studies, diets are formulated to have lower methionine content but supply normal levels of total protein, fat and calories. That’s something easily controlled when feeding lab animals. But implementing this kind of diet for someone who has cancer would require careful attention to ensure they were still meeting nutritional needs and that the diet was acceptable to them.
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Food Choices
People could consider meeting their increased protein needs with foods lower in methionine (pulses such as dry beans and lentils, soy foods, nuts and limited dairy or eggs) rather than boosting high-methionine foods (meat, poultry and fish).
The Importance of Plant-Based Diets
A plant-based diet lower in processed foods has several potential anti-cancer benefits compared to a Western diet (i.e., an animal-based diet higher in processed foods). Higher fiber intake, commonly associated with a plant-based diet, improves a tumor’s response to immunotherapy. A plant-based diet also contains less fats, which are directly associated with increased tumor incidence and progression. Additionally, a low-fat plant-based diet is associated with lower energy intake than a low-carbohydrate animal-based diet, suggesting a plant-based diet could potentially limit energy sources available to tumors. Finally, a plant-based diet contains less protein than animal-based diets, suggesting a potential approach to deprive tumors of amino acids.
Impact on Amino Acid Levels
A study involving patients with metastatic breast cancer found that a whole food, plant-based diet resulted in a lower intake of calories, fat, and amino acids and higher levels of fiber. Additionally, body weight, serum insulin, and IGF were reduced in participants. The diet contained lower levels of essential and non-essential amino acids, except for arginine (glutamine and asparagine were not measured). Importantly, the lowered dietary intake of amino acids translated to reduced serum levels of amino acids in participants.
Ongoing Research and Future Directions
Research investigating methionine’s potential influence on cancer has been under way for decades, but many questions must be answered before methionine reduction can be considered for clinical practice.
Optimal Timing and Level of Methionine Restriction
Research so far supports initiating methionine reduction before chemotherapy or radiation therapy treatment begins so it can reduce levels in the body and sensitize cells to the effects of the lower levels. It’s unclear if methionine reduction can be effective if initiated after starting treatment or whether intermittent use of restricted methionine diets during treatment could have the same benefits. Laboratory studies have tested varying degrees of methionine reduction in the context of cancer research. However, translating these findings to human subjects is a complex task. If methionine reduction is shown to enhance cancer treatment in humans, researchers will then need to identify the ideal methionine level that can do this while supporting overall health.
Clinical Trials
To further explore the potential benefits of methionine reduction in cancer treatment, more human studies are needed. Researchers are actively working on developing ways to make methionine-restricted diets more accessible and feasible. This includes investigating the use of meal replacement shakes or prepackaged meals to simplify the implementation of a methionine-restricted diet. Additionally, researchers are exploring other avenues to reduce body methionine levels, such as the development of enzyme-based pills that can break down methionine.
Considerations for Healthcare Professionals
While awaiting further research, health-care professionals play a critical role in guiding patients who inquire about methionine restriction and putting current evidence in the context of their health and clinical care.
Understanding the Strength of Evidence
People need to understand that for now, most of the evidence is from studies of mice and isolated cell cultures.
Impact on Immunotherapy
Methionine reduction may be more beneficial for therapies that cause DNA damage. Brainson says she would not currently suggest a low-methionine diet for use with immunotherapy; this is a current research priority.
Amount of Added Benefit
For someone with an early-stage cancer, current therapies are so effective that any added benefit from a methionine-restricted diet might be very small. But for someone with late-stage cancer, a modest reduction in tumor burden could make a meaningful difference in lifespan. Health professionals can help patients base their decisions on the best available evidence and not pursue unproven approaches out of a sense of desperation.