Dietary Fat, Fat Metabolizing Genes and Breast Cancer Risk

Institution: University of Southern California
Investigator(s): Sue Ann Ingles, DrPH -
Award Cycle: 2001 (Cycle VII) Grant #: 7WB-0110 Award: $383,740
Award Type: STEP Award
Research Priorities
Etiology and Prevention>Etiology: the role of environment and lifestyle



Initial Award Abstract (2001)
Does a high fat diet increase breast cancer risk? Although this question has been the topic of much research, we still do not know whether decreasing dietary fat might protect against breast cancer. Animal studies and studies of cancer cells grown in the laboratory do support the idea that certain types of fats promote the growth and spread of breast cancer. However, studies of humans have not been convincing. One reason is that many studies have not distinguished between the different types of fats that are consumed in the human diet. Animal studies suggest that it is mainly certain types of polyunsaturated fats (the omega-6 fats that are found in many vegetable oils) that cause cancer, while other types of fats may be harmless or actually protective. Another deficiency of human studies is that genetic differences among individuals have, in previous studies, been ignored. We know, for example, that there are large genetically determined differences among individuals in the regulation of blood cholesterol, a type of fat related to heart disease. While some individuals must carefully monitor their diets, it seems that others are able to eat high fat diets with impunity. With respect to the omega-6 fats that may be related to breast cancer, much less is known about genetic differences. While it is known that genetic differences do exit, the impact on breast cancer risk has not been studied.

Genetically-determined differences among individuals in dietary fat metabolism may influence the development and progression of breast cancer. We hypothesize that by examining genetic and dietary influences together, we may be able to identify dietary risk factors that are obscured when diet is examined in isolation.

We will build on a previous breast cancer study conducted at the Northern California Cancer Center. DNA samples and data on dietary fat intake are already available for more than 750 women diagnosed with breast cancer and 750 women with no history of breast cancer. We will classify these women according to genetic differences that are important for dietary fat metabolism. We will study whether specific types of dietary fat increase risk of breast cancer for women in each of the genetically-determined groups.

This will be the first study to examine specific types of dietary fat in combination with genetic influences on fat metabolism. This study could provide new information to answer the question as to whether breast cancer can be prevented by dietary changes. It may also suggest new ways to treat breast cancer by interfering with the use of fats by breast cancer cells.


Final Report (2004)
Although the question that high fat diet may increase breast cancer risk has been the topic of much research, we still do not know whether decreasing dietary fat might protect against breast cancer. Animal studies and studies of cancer cells grown in the laboratory do support the idea that certain types of fats promote the growth and spread of breast cancer. However, studies of humans have not been convincing. One reason is that many studies have not distinguished between the different types of fats that are consumed in the human diet. Animal studies suggest that it is mainly certain types of polyunsaturated fats (the omega-6 fats that are found in many vegetable oils) that cause cancer, while other types of fats may be harmless or actually protective. Another deficiency of human studies is that genetic differences among individuals have, in previous studies, been ignored. We know, for example, that there are large genetically-determined differences among individuals in the regulation of blood cholesterol, a type of fat related to heart disease. While some individuals must carefully monitor their diets, it seems that others are able to eat high fat diets with impunity. With respect to the omega-6 fats that may be related to breast cancer, much less is known about genetic differences. While it is known that genetic differences do exit, the impact on breast cancer risk has not been studied.

We wish to address two questions: Might genetically-determined differences in dietary fat metabolism influence the development and progression of breast cancer? By examining genetic and dietary influences together, will we be able to identify dietary risk factors that are obscured when diet is examined in isolation?

We have identified 50 common genetic differences in dietary fat metabolizing genes. We have performed functional studies of two of these genetic factors to determine their importance. We have measured nine of these genetic factors (in the 5-LOX; 15-LOX, 12-LOX, and FLAP genes), that are most likely to be important in 814 breast cancer cases and 910 controls in three ethnic populations (non Hispanic white, Hispanic, and African American), and analyzed their associations with breast cancer risk. We found significant associations between some fat metabolizing gene variants and breast cancer risk among certain ethnic populations. We also found that some of the gene variants increase risk of breast cancer only among women with high intake of omega-6 fats.

This is the first study to examine specific types of dietary fat in combination with genetic influences on fat metabolism. Our results suggest an association between genetic difference in certain fat metabolizing genes and increased breast cancer risk, and suggest that diet and genetic differences may work together to impact breast cancer. While the increased risks found are relatively small, our findings provide new evidence that among women consuming high levels of omega-6 fats, such as those found in vegetable oils and processing food, genetic differences may impact breast cancer risk. More studies are needed to determine whether lower intake of omega-6 fats might be beneficial for genetically predisposed women. Our findings also suggest that fat metabolizing enzyme inhibitor drugs may be useful for chemoprevention or treatment.


Symposium Abstract (2003)
A high fat diet has long been suspected as a possible cause of breast cancer. However, even after much research, we still do not know whether decreasing dietary fat might be protective. Animal studies and studies of cancer cells grown in the laboratory do support the idea that certain types of fats promote the growth and spread of breast cancer. However, studies in humans have not been conclusive, perhaps because many studies have not distinguished the different types of fats that are consumed. Animal studies suggest that it is the omega-6 fats, which are found in many vegetable oils, that cause cancer, while other types of fats may be harmless or actually protective. We hypothesize that omega-6 fat may increase breast cancer risk by leading to the formation specific inflammatory products and that genetically-determined differences in omega-6 fat metabolism may influence the development and progression of breast cancer. By examining genetic and dietary influences together, we hope to identify dietary risk factors that are obscured when diet is examined in isolation.

12-LOX is one of the major enzymes of omega-6 fat metabolism. The product of this enzyme has been found to play an important role in breast tumor growth and spread to other organs. We evaluated whether 12-LOX gene variants are associated with breast cancer risk among women participating in a breast cancer study conducted by the Northern California Cancer Center. We found that the risk of breast cancer is about 1.5 times higher for African American women who do not carry the most common 12-LOX gene variant compared to those who do have the common variant. This increased risk is even stronger when we consider the intake of dietary omega-6 fats. Among African American women with the highest dietary omega-6 fat intake (in top 25%), the risk of breast cancer for women lacking this variant is about 2.3 times higher than for those who do carry this variant.

These results suggest that genetic variation in omega-6 fat metabolism may influence breast cancer risk in African American women, and this influence becomes stronger when women consume more omega-6 fats.