Mechanistic insights into reducing the weight of breast cancer.

The prevalence of obesity, an established epidemiologic risk factor for many cancers including breast cancer in postmenopausal women (1), has increased dramatically over the past 30 years (2). Particularly alarming are the increasing rates of obesity among children. Therefore, we can expect continuing increases in the rates of adult obesity and obesity-related cancers for many years to come unless new strategies can be developed for decreasing the harmful, carcinogenic effect of obesity. Unfortunately, the obesity-breast cancer link has not been well-studied. Research on the biological mechanisms underlying the association between obesity and postmenopausal breast cancer, as well as the potential anticancer effects of interventions to prevent or reverse obesity, is urgently needed to develop new strategies to prevent and control obesity-related breast cancers in postmenopausal women. The primary life-style–based interventions to induce negative energy balance (the state at which the number of calories eaten is equal to the number of calories used) and prevent or reverse obesity include a dietary regimen of calorie restriction (3) and increased physical activity (4). Calorie restriction regimens are formulated so that total dietary energy intake is reduced (generally 20-40% lower than usual intake) while micronutrient levels remain constant. Calorie restriction is arguably the most potent and broad-acting dietary intervention for preventing tumors in experimental animals. Calorie restriction inhibits a variety of spontaneous neoplasias in experimental model systems, including tumors arising in several knockout and transgenic mouse models (3). Calorie restriction also suppresses the carcinogenic action of several classes of chemicals, as well as several forms of radiation, in rodents (3). Therefore, the inhibitory action of calorie restriction on carcinogenesis is effective in several species, for a variety of tumor types, and for spontaneously arising tumors as well as chemically and physically induced neoplasias. The limited data in humans and other primates suggest that a moderate calorie restriction regimen also has anticancer effects in higher organisms (5–7). Although less studied than calorie restriction, previous studies of physical activity and mammary tumorigenesis in rodents (most involving chemically induced models) have found beneficial effects of treadmill exercise with intensities higher than 70% of maximal aerobic capacity (VO2 max) for 30 minutes or more (4). This intensity level is roughly equivalent to a fairly vigorous run in a human that would burn ∼400 calories (∼12 metabolic equivalent task [MET] hours; ref. 8). Epidemiologic studies also support the hypothesis that increased physical activity decreases breast cancer risk (9) and improves outcomes in breast cancer patients (10). Potential mechanisms related to physical activity–altered tumor burden have not been adequately examined. Another important knowledge gap is a lack of information on whether the two types of energy-balance–modulating interventions— reduced caloric intake (such as calorie restriction) and increased energy expenditure (such as physical activity)—have an equivalent effect on breast cancer development. It is also unclear whether calorie restriction and physical activity could combine in an additive or synergistic fashion to inhibit breast cancer. Given that over one-third of the current adult U.S. population is obese, information on these matters is urgently needed to guide recommendations to maximize the healthpromoting and cancer-preventive effects of life-style modifications. Furthermore, not everyone can significantly increase their physical activity (due to physical or other limitations) or significantly decrease their caloric intake (which is almost universally difficult in our society for many reasons). Therefore, insights into the mechanisms underlying the effects of calorie restriction and physical activity will reveal new dietary or pharmacologic targets that may be used to mimic or enhance life-style–based strategies for breaking the obesitybreast cancer link. In this issue of the journal, Jiang, Zhu, and Thompson report their results in directly comparing the effects of physical activity with those of a mild restricted energy intake regimen (equivalent to a modest 8-10% calorie restriction) in a 1-methyl-1 nitrosourea–induced rat model (11). They controlled the food intake of their physical activity and restricted energy rats such that both groups had the same net energy balance, resulting in body weights that were 92% of sedentary control rats. This approach allowed the direct comparison of physical activity with restricted energy effects without confounding from differences in net energy balance. They also used an innovative voluntary wheel running system in which the physical activity animals were given free access to an activity wheel, and their voluntary running behavior was encouraged and reinforced via a periodic food reward. This food reinforcement was administered as a predetermined amount using an automated pellet dispenser after a prescribed distance run. The goal was to administer a low-intensity, consistent, and self-determined physical activity regimen that would mimic the national recommendation of 10,000 steps, which is being promoted by several health organizations to encourage all individuals in the United States to wear a pedometer and take 10,000 steps (roughly equal to 5 miles) a day so as to improve overall fitness and help control weight (12). Developed in the Thompson laboratory, this innovative food-reward approach to voluntary wheel running has its own limitations, including Author's Affiliation: Department of Nutritional Sciences, The University of Texas at Austin, and Department of Carcinogenesis, The University of Texas M. D. Anderson Cancer Center, Houston, Texas Received 2/17/09; accepted 3/4/09; published OnlineFirst 3/31/09. Requests for reprints: Stephen D. Hursting. E-mail: [email protected]. edu. ©2009 American Association for Cancer Research. doi:10.1158/1940-6207.CAPR-09-0040