Barrett, J. Carl1; Davis, Barbara J.2; Bennett, L. Michelle1
From the 1Center for Cancer Research, National Cancer Institute, Bethesda, MD, and
2Laboratory of Women’s Health, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC.
Address correspondence to: J. Carl Barrett, Center for Cancer Research, National Cancer Institute, Bldg 31, Room 3A11, 31 Center Drive, MSC-2440, Bethesda, MD 20892-2440; firstname.lastname@example.org
Why is full-term pregnancy protective for breast cancers, ovarian cancers, and as described in this issue of Epidemiology, uterine leiomyomas? 1 Is there a single mechanism or are there multiple mechanisms underlying the protective effects of parity? Are there shared or separate mechanisms that reduce the risk of tumors of the breast, ovary and uterus? The answers to these important questions remain unknown, but the observations of Rostgaard et al.2 on ovarian cancers and Baird and Dunson 1 on uterine fibroids provide some insights and potential new directions of study.
Although parity is consistently protective for all these tumors, the extent of the protective effect varies with age at pregnancy. For breast cancer, pregnancy before the age of 20 results in the greatest protection. 3,4 For ovarian cancer, older age at first pregnancy is more protective. 5,6 Baird and Dunson show that pregnancies at an early age (<25 years) or a late age (≥30 years) have no effect on uterine leiomyomas, whereas a first pregnancy between age 25 and 29 years is protective. 1
The differing effects of age at pregnancy suggest different mechanisms of protection. For breast cancer, there are numerous hypotheses to explain the protective effect of pregnancy, including decreasing responsiveness to carcinogens and mitogens and alterations in cell fate associated with mammary gland differentiation. 7 In the ovary, interruption of incessant ovulation by pregnancy is one possible mechanism. However, pregnancy-associated clearance of premalignant cells is an alternate hypothesis supported by Rostgaard et al.8 The authors carefully note that these hypotheses are not mutually exclusive. Using the simple concept of premalignant cell clearance, Rostgaard et al. provide a model that statistically fits the data from a cohort of 1.5 million Danish women relating reproductive history and ovarian cancer. Baird and Dunson base the explanation of their results, showing only pregnancies at a certain age to be protective, on the hypothesis that postpartum involution of the uterus clears small fibroids during the dramatic remodeling of the tissue. 1 At an early age of pregnancy small fibroids have not formed, whereas at a later age of pregnancy fibroids are larger, making them resistant to the effects of remodeling after parturition.
“. . .changes associated with pregnancy can affect the cancer process at various stages of the multistep process.”
Although these observations and hypotheses may suggest different mechanisms in different tissues, some shared mechanisms may be invoked. Pregnancy and postpartum events have profound effects on the mammary gland, the ovary and the uterus. These tissues undergo remodeling and changes in differentiation. Pregnancy also alters the levels of circulating hormones, including estrogens, progestins and the insulin-like growth factors IGF1 and IGF2. In addition, there are hormones, autocrine growth factors and immune inflammatory cells that have effects on local tissues during pregnancy and the postpartum period. These changes associated with pregnancy can affect the cancer process at various stages of the multistep process. Pregnancy-induced alterations in the differentiation of normal cells limit the cells at risk for cancer initiation. This mechanism is likely important in the breast and possibly the other tissues, although the data in the ovary and uterus are not substantial.
Changes in circulating hormones and local hormone production can profoundly affect the rates of cell division and cell death in precancerous cells. Cancer cells often die at higher rates than normal cells. 9,10 This is particularly true for premalignant cells. 11 Changes in steroids and peptide hormones can have profound effects on the balance of growth and death in premalignant cancers. This is documented as a mechanism for dietary restriction of cancer in experimental animals. For example, modest caloric restriction (20%) in mice reduces circulating IGF1 levels by 25%, which decreases cell proliferation six-fold and increases apoptosis eight-fold in premalignant lesions. This has substantial effects on tumor progression. 12 In the ovary, progestin substantially influences apoptosis of the ovarian epithelium. 13
Future epidemiologic studies of pregnancy should include careful measurements of steroid and peptide hormones. New methods to detect early-stage cancers using serum proteomic markers 14 may assist the evaluation of epidemiologic factors in cancer development. Experimental studies to understand the influence of pregnancy or the differentiation of hormonally responsive tissues may also yield new insights. For example, important changes in gene expression are observed in the mammary epithelium of hormone-exposed animals compared with virgin animals. 15 If pregnancy eliminates or induces cell death in premalignant lesions, this effect would provide a selective pressure for genetically different cancers in parous and nulliparous women. This has implications for epidemiologic studies and therapeutic interventions. As pregnancy has a potent protective influence on several hormonally responsive cancers, a better understanding of the mechanisms for this effect will lead to new insights into etiology, prevention and therapy of these tumors in women.
About the Authors
J. CARL BARRETT is the Director for the Center for Cancer Research at the National Cancer Institute, as well as Chief of the Laboratory of Biosystems and Cancer within the Center. He has had a long-standing interest in hormonal carcinogenesis and the genetic effects of estrogen.
BARBARA J. DAVIS is the Acting Chief of the Laboratory of Women’s Health at the National Institute of Environmental Health Sciences. Her current research interests include the mechanisms of ovarian cancer and uterine tumor development, and pregnancy-induced protection from cancer.
L. MICHELLE BENNETT is the Associate Director for Science in the Center for Cancer Research at the National Cancer Institute. Her research interests include the effects of genetic susceptibility and environmental exposures on breast cancer.
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