Calorie Restriction (CR) Diet

CR & Disease: Breast Cancer Research

September 6, 2009

CR May Provide Some Protection Against Breast Cancer

Following are excerpts and references from animal and human studies of the effects of CR on breast cancer. In all cases the original paper should be read for a full understanding of what was being studied and what could be concluded.

Animal Studies

  1. Title: "Perspectives: Macronutrient Intake and Cancer: How Does Dietary Restriction Influence Tumor Growth and Why Should We Care? "

    Cancer Prevention Research 2, 698, August 1, 2009. Published Online First August 3, 2009; doi: 10.1158/1940-6207.CAPR-09-0134
    Michael Pollak


    "This perspective on the report by Rogozina and colleagues (beginning on page 712 in this issue of the journal) reviews mechanisms that may underlie inhibitory effects of dietary restriction on tumor growth in the mouse mammary tumor virus transforming growth factor alpha (MMTV-TGF-alpha) breast cancer model and comments on the potential clinical relevance of these mechanisms. The inhibitory effect of caloric restriction on carcinogenesis and tumor growth in rodent models is a classic finding that is receiving increasing attention. In some experimental models, the magnitude of the effect is significant, rivaling what can be achieved by pharmacologic approaches to cancer prevention or treatment. Major challenges include defining the underlying mechanisms and determining the clinical relevance of laboratory models of caloric restriction."

  2. Title: "Serum Insulin-like Growth Factor-I and Mammary Tumor Development in Ad libitum–Fed, Chronic Calorie–Restricted, and Intermittent Calorie–Restricted MMTV-TGF- Mice"

    Olga P. Rogozina, Melissa J.L. Bonorden, Joseph P. Grande, and Margot P. Cleary Cancer Prevention Research 2009 2: 712-719.

    Cancer Prevention Research 2009 2: 712-719

    "The effect of chronic (CCR) and intermittent (ICR) caloric restriction on serum insulin-like growth factor (IGF)-I levels and mammary tumor (MT) development was investigated. .... MT incidence was 71.0%, 35.4%, and 9.1% for AL, CCR, and ICR mice. ICR-Restricted mice had significantly lower terminal serum IGF-I and IGF-I/IGF binding protein-3 (IGFBP-3) ratio than CCR, ICR-Refed, and AL mice. ....For all groups, elevated IGF-I levels preceded MT detection, although not all values were significant versus mice without MTs. However, the specific role of IGF-I in the protective effect of calorie restriction remains to be determined. These results confirm that ICR prevents MT development to a greater extent than CCR."

  3. Newspaper Article in Ventura County Star on July 3, 2006 by Margaret Nesbit [research paper unidentified]

    "In the early '80s, I had the privilege of working with Dr. Roy Walford, a pioneer in the field of gerontology...In his vivarium at UCLA, in an experiment with mice genetically programmed to get breast cancer, the malignancy rates were reduced from an expected 55 percent to 5 percent or less when a calorie restricted diet was administered."

  4. Title: "2-Deoxyglucose as an energy restriction mimetic agent: effects on mammary carcinogenesis and on mammary tumor cell growth in vitro."

    Cancer Research. 65(15):7023-30, 2005 Aug 1.; Zhu, Zongjian. Jiang, Weiqin. McGinley, John N. Thompson, Henry J.

    PMID: 16061689

    "Dietary energy restriction (DER) is a potent inhibitor of carcinogenesis, but chronic DER in human populations is difficult to sustain. Consequently, interest exists in identifying energy restriction mimetic agents (ERMAs), agents that provide the health benefits of DER without reducing caloric intake..."

    "These studies support the hypothesis that DER inhibits carcinogenesis, in part, by limiting glucose availability and that energy metabolism is a target for the development of ERMA for chemoprevention."

  5. Title: "Effects of dietary energy repletion and IGF-1 infusion on the inhibition of mammary carcinogenesis by dietary energy restriction."

    Molecular Carcinogenesis. 42(3):170-6, 2005 Mar.; Zhu, Zongjian. Jiang, Weiqin. McGinley, John. Wolfe, Pamela. Thompson, Henry J.

    PMID: 15599926

    "Dietary energy restriction (DER) is a potent inhibitor of mammary carcinogenesis, but the responsible mechanisms are not fully understood. In a number of model systems, DER is associated with a decrease in circulating levels of IGF-1. Moreover, we have recently reported that protection against cancer is lost, and plasma IGF-1 levels are restored to control values when animals are re-fed, i.e., energy repleted (DER-REP). Accordingly, an experiment was designed to determine if infusion of IGF-1 could mimic the effect of DER-REP on the carcinogenic response in animals that were DER. .."

    "Thus, an 8-d period of refeeding following chronic DER (DER-REP) reversed the anticancer effects of DER, and 8 d of IGF-1 infusion without refeeding (INF) did not mimic the effects of the DER-REP on the carcinogenic response. (c) 2004 Wiley-Liss, Inc."

  6. Title: "Adrenalectomy does not block the inhibition of mammary carcinogenesis by dietary energy restriction in rats."

    Journal of Nutrition. 134(5):1152-6, 2004 May.; Jiang, Weiqin. Zhu, Zongjian. McGinley, John N. Thompson, Henry J.

    PMID: 15113962

    "Dietary energy restriction (DER) has been shown to reproducibly inhibit chemically induced mammary carcinogenesis. The inhibitory activity of DER has been reported to be associated with an increase in circulating corticosterone as well as a decrease in insulin-like growth factor 1 (IGF-1). To determine whether the adrenal glands are required for cancer inhibitory activity, the effects of DER were investigated in adrenalectomized (ADX) rats..."

    "Collectively, these findings indicate that adrenal glands are not required for manifestation of the cancer inhibitory activity of DER."

  7. Title: "Mechanisms by which energy restriction inhibits rat mammary carcinogenesis: in vivo effects of corticosterone on cell cycle machinery in mammary carcinomas."

    Carcinogenesis. 24(7):1225-31, 2003 Jul.; Zhu, Zongjian. Jiang, Weiqin. Thompson, Henry J.

    PMID: 12807724

    "Increased secretion of adrenal cortical steroids may account in part for its cancer inhibitory activity of energy restriction (ER). To test this hypothesis, a study was conducted to determine the effects of dietary administration of corticosterone on the post-initiation stage of mammary carcinogenesis. .."

    "Whereas the effects of exogenously administered corticosterone and ER had many similarities, the lower efficacy of corticosterone versus ER in inhibiting the carcinogenic process imply that changes in cortical steroid metabolism alone are unlikely to explain the cancer inhibitory activity of ER."

  8. Title: "Effect of energy restriction on cell cycle machinery in 1-methyl-1-nitrosourea-induced mammary carcinomas in rats."

    Cancer Research. 63(6):1228-34, 2003 Mar 15.; Jiang, Weiqin. Zhu, Zongjian. Thompson, Henry J.

    PMID: 12649181

    "Energy restriction (ER) results in a profound inhibition of chemically induced mammary carcinogenesis. The cancer inhibitory activity of ER has been shown to be associated with lower rates of cell proliferation during both premalignant and malignant stages of this disease process. .."

    "These observations are consistent with the hypothesis that ER exerts its profound cancer inhibitory activity, in part, by multifaceted regulation of cell cycle machinery, possibly via concomitant changes in corticosterone and IGF-1 metabolism, although the role of other hormones and growth factors should not be dismissed."

  9. Title: "An experimental paradigm for studying the cellular and molecular mechanisms of cancer inhibition by energy restriction."

    Molecular Carcinogenesis. 35(2):51-6, 2002 Oct.; Zhu, Zongjian. Jiang, Weiqin. Thompson, Henry J.

    PMID: 12325034

    "With a rapid-emergence, chemically induced animal model for breast cancer, an experiment designed to test the hypothesis that energy restriction (ER) induces the loss of carcinogen-initiated cells from the mammary gland, thereby conferring a permanent protective effect against the development of cancer, failed to support this hypothesis. .."

Human Studies

  1. Title: "Caloric Restriction and Incidence of Breast Cancer"

    JAMA. 2004;291:1226-1230.; Vol. 291 No. 10, March 10, 2004; Karin B. Michels, ScD, MSc, MPH; Anders Ekbom, MD, PhD

    PMID: unknown, this is link to abstract

    "Objective To determine whether caloric restriction in early life reduces the risk of invasive breast cancer."

    "Design, Setting, and Participants Retrospective cohort study using data from the Swedish Inpatient Registry, the Swedish Cancer Registry, the Swedish Death Registry, and the Swedish Fertility Registry. Participants were 7303 Swedish women hospitalized for anorexia nervosa prior to age 40 years between 1965 and 1998..."

    "Conclusions Severe caloric restriction in humans may confer protection from invasive breast cancer. Low caloric intake prior to first birth followed by a subsequent pregnancy appears to be associated with an even more pronounced reduction in risk."

  2. Title: "Insulin, Physical Activity, and Caloric Intake in Postmenopausal Women: Breast Cancer Implications."

    Journal of Clinical Oncology. 22(22):4507-4513, November 15, 2004.; Chlebowski, Rowan T.; Pettinger, Mary; Stefanick, Marcia L.; Howard, Barbara V.; Mossavar-Rahmani, Yasmin; McTiernan, Anne

    PMID: 15542801

    "Purpose: Increased physical activity and programs to reduce body mass index (BMI) with both increased physical activity and decreased caloric intake have been proposed to reduce insulin as a potential mediator of breast cancer and other chronic diseases. However, there are few data on the relative contribution of physical activity, caloric intake, and BMI to fasting insulin levels."

    "Conclusion: These findings suggest that reduction in BMI achieved by increasing physical activity, reducing caloric intake, or both, should lower insulin levels, providing support for clinical trials evaluating insulin level change and breast cancer risk."

  3. Title: "Breast Cancer Risk After Caloric Restriction During the 1944-1945 Dutch Famine."

    Journal of the National Cancer Institute. 96(7):539-546, April 7, 2004.; Elias, Sjoerd G.; Peeters, Petra H. M.; Grobbee, Diederick E.; van Noord, Paulus A. H.

    PMID: 15069116

    "Background: Data from animal models suggest that caloric restriction may reduce the risk of breast cancer, although not all dietary regimens produce similar effects. We examined whether caloric restriction imposed as a consequence of the 1944-1945 Dutch famine reduced the risk of breast cancer in women participating in a Dutch breast cancer screening program."

    "Conclusions: The risk of breast cancer was increased in women who were severely exposed to a short but severe famine decades earlier. This result is compatible with data from the few animal studies investigating effects of short-term, transient caloric restriction."

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