Horm Mol Biol Clin Invest 2012;9(1):11–23 © 2012 by Walter de Gruyter • Berlin • Boston. DOI 10.1515/hmbci-2012-0019 Pregnancy hormonal environment and mother’ s breast cancer risk Leena Hilakivi-Clarke 1, *, Sonia de Assis 1 , Anni Warri 1 and Riitta Luoto 2 1 Lombardi Cancer Center, Georgetown University, Washington, DC, USA 2 UKK Institute for Health Promotion, Tampere, Finland Abstract Pregnancy can both reduce and increase lifetime breast can- cer risk, and it also induces a short-term, transient increase in risk. Several biological mechanisms have been proposed to explain the protective effect, including pregnancy-induced increase in circulating estrogen levels leading to reduced estrogen receptor (ER) expression and activity. Persistent changes in ER-regulated gene expression may then alter the response of the breast to postpregnancy hormonal expo- sures originating, for example, from food. Understanding how pregnancy increases breast cancer risk has received less attention. Human studies indicate that those women who were exposed to an elevated pregnancy estrogenic environment, such as women who took the synthetic estrogen diethylstil- bestrol or who had the highest circulating estrogen levels at the beginning or end of pregnancy, are at increased risk of developing breast cancer. There is also evidence that elevated leptin levels, for example, in pregnant women who gained excessive amount of weight, increase later breast cancer risk. This may reflect a close interaction between estradiol (E2), ER, and leptin. Our preclinical study suggests that an exposure to excess pregnancy E2 and leptin levels reverses the protective changes in genomic signaling pathways seen in the breast/mammary gland of parous women and rodents. Recent findings indicate that involution – the period after lac- tation when the breast regresses back to prepregnancy stage – may be related to some pregnancy-associated breast can- cers. Importantly, in a preclinical model, the increase can be reversed by anti-inflammatory treatment, offering hope that the increase in lifelong breast cancer risk induced by late first pregnancy or by an exposure of pregnant women to an exces- sive hormonal environment may be reversible. Keywords: breast cancer; estradiol; leptin; pregnancy. Introduction Several reproductive and lifestyle factors have been linked to altered breast cancer risk, including pregnancy [1, 2]. Pregnancy has a dual effect on breast cancer. It provides a strong protective effect – 50% reduction in risk – if the mother is younger than 20 years of age at the time of her first full-term pregnancy, compared to women who are over 30 [2]. Furthermore, women who have their first child after the age of 30 have a significantly higher lifetime risk of developing breast cancer risk than nulliparous women [1, 3]. Pregnancy also induces a short-term increase in risk in all women, regard- less of their age [4–7]. Within the first year after pregnancy, the risk of developing breast cancer is increased by 20-fold [5]. The increased risk is estimated to last approximately 5–10 years following the last full-term pregnancy [4–6], after which the risk returns to the appropriate lifetime level. The protective effect of pregnancy is limited to estrogen and progesterone receptor-positive (ER+ and PR+) breast cancers [8, 9]. In contrast, the increase in breast cancer risk following pregnancy applies mostly to ER-negative (ER-) breast cancers [9], although an increase in ER+/PR+ breast cancers in older first-time mothers has been reported [10]. These findings sug- gest that the increase in pregnancy estrogen levels protects against breast cancer, while the majority of pregnancy-associ- ated breast cancer (PABC) occur independently of the marked increase in hormone levels that characterize pregnancy. This interpretation is likely too simplistic, because accumulating evidence indicates that hormonal exposures during pregnancy increase a mother’s later risk of developing breast cancer (see below). As pregnancy can both reduce and increase the risk of breast cancer, it is important to determine the mechanisms by which this happens. Our review will summarize the existing literature on the proposed biological pathways linking preg- nancy to breast cancer risk. At the end, we briefly discuss the “safety” of pregnancy after breast cancer. Why does early pregnancy reduce breast cancer risk? Several explanations have been provided as to why early preg- nancy reduces breast cancer risk, and they have been reviewed extensively elsewhere [11, 12]. We will focus on three mecha- nisms. First, it has been suggested that the hormonal environ- ment of pregnancy, particularly high estrogen levels, result in a reduction in breast cancer risk [13]. High estrogen levels dur- ing pregnancy may alter the sensitivity of the mammary gland to later hormonal exposures [11]. Second, pregnancy is known *Corresponding author: Leena Hilakivi-Clarke, Lombardi Cancer Center, Georgetown University, Research Building, Room E407, 3970 Reservoir Road, NW, Washington, DC 20057, USA Phone: +1-202-687-7237, E-mail: clarkel@georgetown.edu Received March 13, 2012; accepted March 19, 2012; previously published online April 9, 2012 Brought to you by | Georgetown University (Georgetown University) Authenticated | 172.16.1.226 Download Date | 6/13/12 7:09 PM