Fish Oils May Slow Breast Cancer Growth via Immune, Inflammatory Mechanisms

Past epidemiological studies have suggested that women who consume high levels of long-chain omega-3 fatty acids (LC-ω-3FA) have a lower risk of developing breast cancer (BC) than women who consume low levels of omega-3. New research in mice suggests that a diet rich in long-chain omega-3 fatty acids can suppress the growth and metastasis of breast cancer, and prolong survival, by suppressing tumor-promoting inflammation and boosting anticancer T-cell responses.

The scientists, headed by Saraswoti Khadge, Ph.D., at the University of Nebraska Medical Center, are not claiming that their findings suggest that women who eat an omega-3-rich diet will be protected from developing breast cancer. Rather, Dr. Khadge states, “Our study emphasizes the potential therapeutic role of dietary long-chain omega-3 fatty acids in the control of tumor growth and metastasis.”

The scientists reported on their studies in Clinical & Experimental Metastasis, in a paper titled, “Long-chain omega-3 polyunsaturated fatty acids decrease mammary tumor growth, multi-organ metastasis and enhance survival.”

Breast cancer is one of the leading causes of cancer deaths in women in the U.S., the authors comment. However, there is a significant difference in breast cancer incidence between populations who eat typically western diets, and those consuming Asian diets, “typically due to a higher intake of fish, supporting dietary polyunsaturated fatty acid (PUFA) composition as a risk factor for BC.” Western diets tend to contain higher levels of omega-6 fatty acids relative to omega-3 fatty acids, and while metabolites of long-chain omega-3 fatty acids, including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are metabolized to lipid mediating compounds that are “important in inflammation resolution,” the omega-6 fatty acid metabolites such as arachidonic acid (AA) are pro-inflammatory mediators. “ … chronic production of AA has been associated with inflammation-associated morbidity including BC patients,” the team points out.

Prior studies in mice have found that a diet rich in omega-3 given early in life reduces the incidence and growth of mammary tumors when compared with diets high in omega-6 fatty acids. Studies have also shown that adult mice fed omega-3-high diets exhibit reduced mammary gland (MG) ductal density, proliferation of MG epithelial cells, and fat tissue inflammation, which are all associated with lower risk of breast cancer. However, what hasn’t yet been studied to any great degree, the authors write, is whether dietary long-chain omega-3 fatty acids impact on the regulation of mammary tumor microenvironments, tumor progression, metastasis, or survival. They hypothesized that a diet rich in omega-3 fatty might suppress mammary tumor cell proliferation and metastasis by modulating tumor and metastatic microenvironments.

To investigate this idea they fed 10-week-old mice female mice on diets that were high either in omega-3 fatty acids or omega-6 fatty acids, but which were identical in overall calorie and fat content.  After 16 weeks on their respective diets the animals were injected with 4T1 breast cancer cells, a cell line that develops into aggressive breast tumors and readily metastasizes to multiple organs.  The animals’ resulting tumors, metastases, and tumor microenvironments were then assessed 35 days after injection of the breast cancer cells.

The results showed that tumors took longer to develop and were on average 50% smaller at day 35 in mice consuming the high omega-3 diet, compared with animals in omega-6 groups. Consumption of the omega-3 diet was also associated with up a 64% lower incidence of lung metastases, and 47% lower incidence of metastases to the liver. The development of metastases in other, less common metastatic sites, including bone, heart, kidneys, and ovaries, was up to 87% lower among the omega-3 mice, and animals in the omega-3 groups also lived for significantly longer than those in the omega-6 groups. Encouragingly, two of the 40 mice in the omega-3 fatty acid group didn’t develop any breast tumors, whereas all of the omega-6 mice did develop tumors.

Mice that had been fed the omega-3-rich diet prior to cancer cell injection also exhibited much lower levels of tumor inflammation. Analyses showed that tumors in these animals were associated with 44% fewer proliferating primary tumor cells, higher numbers of apoptotic breast cancer cells, and greater numbers of T cells, as well as reduced neovascularization, and sixfold higher levels of tumor IL10 mRNA, which “inversely correlated with the tumor size,” the authors write. “These data suggest a potential role for dietary LC-ω-3FAs in the regulation of tumor and systemic inflammation via IL10 mediated pathways,” they suggest. “The surrogate analyses undertaken support a mechanism of action by dietary LC-ω-3FAs that includes, but is not limited to decreased infiltration by myeloid cells (neutrophils and macrophages), an increase in CD3+ lymphocyte infiltration, and IL10 associated anti-inflammatory activity … Our finding of a greater number of T cells and fewer neutrophils in tumors from mice fed a diet rich in LC-ω-FAs, relative to the numbers in the ω-6 diet group and a direct correlation of NLR [neutrophil to lymphocyte ratio] with tumor size, indicates the potential of dietary LC-ω-3FAs in tumor growth suppression by decreasing tumor supporting inflammation.”

Given that the animals were fed their omega-3, or omega-6 diets before receiving the breast cancer cell injections, the researchers suggest that the dietary omega-6 may have a prophylactic role in controlling tumor growth and metastasis.  “… we conclude that dietary LC-ω-3FAs suppress mammary tumor growth resulting in lower frequency of metastasis to the preferential metastatic sites such as lungs and prolonged survival of the mice,” they state. “Moreover, considering the differences in metastatic burden (incidence/frequency and size) in multiple organs (specifically low preferential sites; heart, kidney, ovaries, bone, and CMGs) between the ω-3 and ω-6 dietary groups, out data indicate dietary PUFA composition has additive effects in metastasis, in addition to the regulation of metastasis by primary tumor growth.”