Fatty acids and breast cancer: Sensitization to treatments and prevention of metastatic re-growth

Abstract

Lifestyle and nutritional factors have been recognized to influence breast cancer survival, irrespective of genomic alterations that are the hallmarks of the disease. The biological and molecular mechanisms involved in the effects of dietary polyunsaturated fatty acids and breast cancer response to treatments in clinical and preclinical studies have been reviewed. Among nutrients, rumenic acid, a naturally occurring CLA isomer and n-3 docosahexaenoic acid (DHA) a highly unsaturated fatty acid, have emerged due to their potential to increase cancer treatment efficacy without additional side effects. In this review, we analyze the literature evidence that breast cancer treatment and outcome could be improved through an adjuvant dietary supplementation. Such an original approach would involve two successive phases of breast cancer treatment: an initial sensitization of residual tumor cells to chemotherapy and to radiation therapy with dietary DHA; then a prevention of metastatic re-growth with a prolonged rumenic acid supplementation. Safety is not anticipated to be a critical issue, although it has to be assessed in the long term. Dietary supplements, used in combination to anti-cancer agents, should be provided under medical prescription. Such an original use of fatty acids in breast cancer treatment could provide the lipid field with a new avenue to impact public health.

Introduction

Dietary lipids are major determinants of the overall lipid composition of storage lipids and also of membrane lipids, as assessed during dietary intervention studies carried out in animals [1], [2], [3] and human [4], [5], [6], [7]. Due to the relation of the fatty acid composition of cell membrane phospholipids to cellular functions, the interest into the identification of the health effects of dietary changes in fatty acid intake has been growing.

Polyunsaturated fatty acids (PUFAs) are a subclass of bioactive components (see http://www.lipidmaps.org/) divided in two groups (n-6 and n-3 fatty acids) which have been studied in the context of cancer prevention. The n-6 series includes a precursor, linoleic acid (LA, 18:2n-6), abundant in food of animal origin, in vegetables and in oils such as sunflower, soy bean and grape seed. It also comprises the arachidonic acid (AA, 20:4n-6), which is a substrate of specific lipid oxygenases to form bioactive inflammatory mediators, and the gamma-linolenic acid (GLA, 18:3n-6) found in several vegetable sources. The n-3 series includes an essential fatty acid, the alpha-linolenic acid (ALA, 18:3n-3) found in green vegetables and in several oils (colza, soybean), and highly unsaturated derivatives such as the eicosapentaenoic acid (EPA, 20:5n-3) and the docosahexaenoic acid (DHA, 22:6n-3). Those are ubiquitous in mammals and abundant in seafood and marine products. n-3 and n-6 fatty acids participate to the biosynthesis of bioactive oxygenated derivatives.

Among other fatty acids with relevance to cancer prevention are the conjugated linoleic acids (CLA). CLA is a generic term to describe positional and geometrical isomers of linoleic acid with a conjugated double bond system. CLA are naturally present in many food items, including dairy products and meat from ruminants [8], where their biosynthesis results from biohydrogenation of polyunsaturated fatty acids (linoleic or alpha-linolenic acids) by the rumen flora. The principal isomer formed in ruminants is the cis-9, trans-11 CLA, also named rumenic acid. It represents 80–90% of CLA in milk products. This isomer can also be produced, in animals and humans, from the bioconversion (delta-9 desaturation) of vaccenic acid (trans-11 18:1) [9]. In the food industry, the main isomers produced are trans–trans: trans-10, trans-12 and trans-9, trans-11 CLA. Specific mixtures of different isomers such as cis-9, trans-11 and trans-10, cis-12 have been chemically synthesized and are available for preclinical or clinical studies.

This review addresses the effects of the interaction of dietary PUFAs and breast cancer in terms of clinical outcome and mechanistic features. Breast cancer remains a major public health problem with more than 1 million incident cases a year in the world, nearly half being in North America and Europe [10]. The prognosis of this disease relies on the characteristics of the tumor and on the quality of the treatments. These treatments consist of both loco-regional and systemic approaches, based on chemotherapy and then on hormonal manipulation, to avoid or delay the occurrence of metastases [11].

Loco-regional treatments consist of surgically removing the tumor and the axillary lymph nodes. Prevention of local relapses relies on the eradication of focal residual tumor cells within the operated area by radiation therapy. Recurrence within distant organs, namely metastases, is particularly feared in breast cancer because their occurrence makes the disease no longer amenable to curative treatment. It has been admitted for decades that tumor cells escaped from the primary breast tumor, disseminate in the body and proliferate within other organs to form new tumors. Systemic treatments, such as chemo- or hormonal therapy, have been used with the aim of preventing tumor re-growth and the development of metastases. The goal of chemotherapy is to eradicate the disseminated tumor cells, while hormonal therapy aims at keeping those cells in a dormant state. The frequent appearance of late metastases, occurring more than 5 years after the end of treatment, is a feature specific to breast cancer. Although not addressed in this review, one has to bear in mind that this model for breast cancer distant recurrence is currently being reassessed by new, emerging, concepts such as the putative involvement of stem cells or epithelial mesenchymal transition [12], [13].

Local relapses and metastases make breast cancer a deadly disease. Despite better quality treatments, the rate of recurrences is still high and consequently breast cancer remains the second leading cause of cancer-related death in women, with a yearly toll of more than 40,000 deaths in the United States, and 11,000 in France (http://www-dep.iarc.fr/). This illustrates dramatically the failure of our current treatments to prevent tumor re-growth from residual tumor cells, locally or at distant sites. Latest improvements in surgery or radiation therapy have led to a decreased morbidity, with better cosmetic and functional results, but there have been no remarkable changes in the relapse rates. Progress in systemic treatments have led to a reduced rate of metastases, principally in those breast cancers holding specific molecular alterations amenable to targeted therapies. For example, trastuzumab (Herceptin™) has been used for tumors over-expressing HER2 (a receptor to the epidermal growth factor), but those represent only 10% of breast cancers. Whereas molecular-targeted therapies permitted significant advances, the wide variability of the genomic alterations of breast tumors remains a pitfall for the improvement of breast cancer treatments by restraining the use of these therapeutic approaches to a small subset of patients [14]. In addition, all these recently developed therapies have their own side-effects, resulting from their toxicity to non-tumor tissues. Beside approaches focused on the tumor cell, many recent studies have stressed that the environment of the tumor (the microenvironment) [15] as well as the environment of the host (the patient), are major determinants of the tumor fate [16]. A major goal for future breast cancer treatments remains the improvement of treatment efficacy, meaning increasing toxicity to tumor tissue, without additional toxicity to non-tumor tissues. Therefore further efforts should aim at identifying agents and/or original approaches with enhanced specificity toward tumor tissues.

Diet, and particularly dietary lipids, have long been studied in association with breast cancer survival and recurrence [16], [17]. The role of dietary lipids in breast cancer has been investigated in two large controlled intervention trials [18], [19], one of which (WHEL study) was inconclusive. In contrast, the Women’s Intervention Nutrition Study (WINS) provided evidence that dietary lipids may influence local or distant recurrences, and in turn influence survivorship. In this cohort of nearly 2500 women already treated for an early breast cancer, the reduction of the dietary fat intake to 22% of the total energy intake [19] led to a reduction of the rate of recurrences by 24%. This intervention study highlighted for the first time the fact that diet influenced survivorship. It also indicated that a dietary intervention, solely based on a quantitative change in total dietary fat intake, can modify breast cancer outcome to an extent close to what is achievable by the current adjuvant treatments. Therefore, it has been thought that a dietary intervention targeting precisely identified individual lipids might produce even greater benefits than gross changes in the diet.

Animal models addressing this issue rely on the evaluation of the effects of lipid components in the diet on either the inhibition of mammary tumor growth or the prevention of tumor appearance. The experimental models used included mice or rats treated with a dietary PUFA and either transplanted with tumors or subjected to chemical carcinogenesis. The lipids were generally provided as a mixture of several different fatty acids. Interactions between PUFA and other lipid constituents of the mixture probably influenced the overcome of the diet. At least for those two reasons, it has been difficult to make conclusions, from these nutritional studies, about the involvement of specific PUFA on tumor growth. Despite these controversial results, it is generally admitted that n-6 PUFA tend to have a mammary tumor enhancing effect and several animal studies have reported an antineoplastic role of n-3 PUFA.

In a seminal article, it has been examined whether there was a relation between breast cancer evolution subsequent to treatment (with the occurrence of metastases as the endpoint) and dietary fatty acids intake. Those were evaluated by analyzing adipose tissue fatty acid composition from breast biopsies, reflecting past fatty acid intake [20]. A prospective study with 123 patients who had completed a loco-regional treatment for localized breast cancer was conducted and adipose tissue was sampled during the initial surgery. With a mean follow-up of 32 months, 21 patients developed metastases subsequent to treatment. After multivariate analysis and adjustment for the main prognostic factors, we found that the likelihood to develop metastases was 4.3-fold higher in patients with alpha-linolenic acid (ALA, 18:3n-3) level in the adipose tissue lower than the median value of the entire population [21]. There was also a trend for a protective effect of long chain n-3 PUFAs, which included DHA. Thus, for the first time, a component of the host, the fatty acid profile of the adipose tissue, could be related to the prognosis of the disease.

These data relating the fatty acid profile of storage lipids to breast cancer survivorship were indicative that diet, and not only the genomic alterations of the tumor, could influence the metastatic risk by preventing tumor re-growth. Since tumor re-growth also depends on the efficacy of cancer treatments, a working hypothesis has been that identified dietary factors, such as PUFA, may influence the efficacy of radio- or chemotherapy.

This review compiles the scientific and medical evidence relating dietary PUFA, in particular DHA and CLA, to breast cancer evolution subsequent to treatment. The literature indicates that DHA sensitizes breast malignant tumors, but not non-tumor tissues, to chemotherapy and to radiotherapy through a variety of mechanisms, and that CLA has the potential to prevent tumor re-growth. We therefore consider the possibility for a combination of these natural dietary compounds with currently recognized standard breast cancer treatments.