Progesterone
Progesterone exerts powerful influences on breast physiology and can influence tumor development in rodents. Based largely on indirect evidence, progesterone has been hypothesized both to decrease breast cancer risk by opposing estrogenic stimulation of the breast and to increase risk because breast mitotic rates are highest in the luteal (high-progesterone) phase of the menstrual cycle. In one prospective study, serum progesterone was 95% higher in cases compared with controls in the luteal phase and 20% higher in the follicular phase; however, the study was small (22 cases), and the differences were not statistically significant. A nonsignificant inverse association between progesterone and breast cancer has been reported in an additionalprospective analysis. Additional larger studies are needed to address this relationship in detail.

Prolactin
Indirect evidence suggests that prolactin could play a role in breast carcinogenesis. Prolactin receptors have been found in more than 50% of breast tumors, and prolactin increases the growth of both normal and malignant breast cells in vitro, although these findings have not been entirely consistent. Prolactin administration is well documented to increase mammary tumor rates in mice.

A number of case control studies of prolactin levels and breast cancer risk have been conducted, although the largest of these included just 66 cases. Also, because prolactin is influenced by both physical and emotional stress, levels in women with breast cancer may not reflect their predisease levels. Thus, evaluation of this association in prospective studies is particularly important. Only two prospective studies have been conducted. In the first, which included 40 postmenopausal breast cancer cases, women in the top quintile of prolactin levels had a nonsignificant 63% higher risk of breast cancer compared with those in the bottom quintile. In a prospective analysis of prolactin and breast cancer risk from the Nurses’ Health Study that included 306 postmenopausal cases and 448 postmenopausal controls, a significant positive association was seen (top versus bottom quartile comparison: relative risk, 2.0; 95% confidence interval, 1.2 to 3.3; p for trend = .01).

Epidemiologic data on premenopausal prolactin levels and breast cancer risk are more sparse, and results are inconsistent. In the only prospective study, with 71 cases, no relationship was observed, although confidence limits were wide (top versus bottom quintile comparison: relative risk, 1.1; 95% confidence interval, 0.5 to 2.2). Thus, no conclusion can be drawn as to the relationship between prolactin levels and breast cancer risk in premenopausal women.

Insulinlike Growth Factor
Insulinlike growth factor type I (IGF-I) is a polypeptide hormone with structural homology to insulin, and it is regulated primarily by growth hormone. Evidence is increasing that the growth hormone-IGF-I axis stimulates proliferation of both breast cancer and normal breast epithelial cells. Transgenic mice that overexpress growth hormone exhibit a high frequency of breast cancer, and rhesus monkeys treated with growth hormone or IGF-I show histologic evidence of mammary gland hyperplasia. In addition, positive associations have been observed between breast cancer and both birth weight and height, which are both positively correlated with IGF-I level.

The relationships between blood levels of IGF-I and its major binding protein, insulinlike growth factor binding protein 3 (IGFBP-3), have been evaluated in several epidemiologic studies. In two case control studies, a positive relationship was noted between plasma IGF-I levels and breast cancer risk. In the larger of the two studies (with 109 cases), the relationship was strongest among premenopausal women. In the Nurses’ Health Study, plasma levels in 397 women with invasive breast cancer (diagnosed after they provided a blood sample) were compared with those of 620 age-matched controls. No association was noted between IGF-I level and risk in postmenopausal women. A positive relationship was observed, however, between premenopausal IGF-I levels and risk (top versus bottom tertile, controlling for IGFBP-3: relative risk, 2.9; 95% confidence interval,1.2 to 6.9); this relationship was particularly strong among premenopausal women under age 50 years (relative risk, 7.3; 95% confidence interval, 2.4 to 22.0), although these analyses included few cases.

The difference in RRs between premenopausal and postmenopausal women, observed in two of the three studies published to date, may reflect a relatively important effect of the growth hormone-IGF-I axis earlier in life after breast development. Alternatively, IGF-I levels may be specifically relevant to risk of premenopausal breast cancer, perhaps because estradiol may enhance IGF-I activity in the breast. Although these findings relating plasma levels of IGF-I (and IGFBP-3) to breast cancer are promising, they require further confirmation in larger studies, particularly in studies among premenopausal women.

Prenatal Risk Factors
In utero exposure to circulating hormones has been hypothesized to influence the fetus’s breast cancer risk in adulthood, perhaps through the influence of these levels on the number and degree of differentiation of breast stem cells. To address this hypothesis, factors such as birth weight and occurrence of preeclampsia, known to be associated with hormone levels during pregnancy, have been evaluated in relation to breast cancer risk. Data are relatively consistent in showing a positive association between birth weight and breast cancer. Strong inverse associations between preeclampsia and disease risk also have been reported. Findings for other measures of in utero hormone exposure, however (e.g., maternal smoking behavior, birth order), have been less consistent. Overall, increasing evidence suggests some influence of in utero exposures on subsequent risk of breast cancer.

Walter C. Willett, Beverly Rockhill, Susan E. Hankinson, David J. Hunter and Graham A. Colditz

W. C. Willett: Harvard Medical School, Boston, Massachusetts; Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts
B. Rockhill: Harvard Medical School, Brigham and Women’s Hospital, Boston, Massachusetts
S. E. Hankinson: Departments of Medicine and Epidemiology, Harvard Medical School and Harvard School of Public Health, Boston Massachusetts
D. J. Hunter: Departments of Epidemiology and Nutrition, Harvard School of Public Health, Boston, Massachussetts
G. A. Colditz: Department of Medicine, Harvard Medical School, Boston, Massachussetts

References