Mini-reviewProlactin and breast cancer risk
Introduction
Prolactin is a polypeptide hormone that is important in the proliferation and differentiation of normal mammary epithelium as well as in stimulating lactation [1], [2]. It is also involved in maintaining the salt-water balance and is a stimulatory modulator of immune function [1]. Prolactin levels increase during pregnancy and, in conjunction with estrogens and progesterone, lead to full lobuloalveolar development of the breasts [3]. Shortly after pregnancy, high prolactin levels are necessary to stimulate lactation, although after several months, lactation is maintained by normal non-pregnancy levels [4]. Prolactin inhibits the release of gonadotropin-releasing hormone, which suppresses ovulation during lactation [1], [4]. In non-lactating women, hyperprolactinemia can lead to galactorrhea and amenorrhea [3].
Prolactin is primarily produced in the pituitary gland, and its regulation is complex and not completely understood. Important acute stimulators of circulating prolactin levels include pregnancy, breast feeding, surgical and psychological stress, strenuous exercise, estrogen, and hypothyroidism; the primary inhibitor is dopamine [1], [4]. Prolactin also has a diurnal pattern, with levels increasing after sleep initiation [3]. Recent evidence suggests that prolactin is locally produced within several target organs, including breast tissue, the endometrial lining, and T-cells [5], [6], [7]. Further, prolactin may act as an autocrine/paracrine factor within mammary tissue [2], [8], [9]. Several studies have demonstrated that prolactin mRNA is produced in normal human breast epithelium [10], [11] and that breast cancer cells can synthesize appreciable quantities of prolactin in vitro [6], [9], [11], [12]. Little is known about the relationship between blood and breast tissue prolactin concentrations; however prolactin staining in breast tumors was significantly correlated (r=0.41) with plasma prolactin concentrations at the time of diagnosis in one report [13].
In the 1980s several clinical trials were conducted to examine whether drugs that reduced prolactin levels could be used as a treatment for breast cancer. The trials were unsuccessful, probably because the drugs only inhibited pituitary prolactin production, rather than breast tissue specific production. More recently, a number of animal and in vitro studies have suggested that prolactin may be involved in mammary tumorigenesis [2] by promoting cell proliferation and survival [14], [15], [16], [17], increasing cell motility [18], and supporting tumor vascularization [2], [19]. Additionally several epidemiologic studies have reported that prolactin levels were positively associated with breast cancer risk [2]. This review discusses laboratory data supporting a role of prolactin in breast cancer etiology and epidemiologic studies relating prolactin to breast cancer risk, as well as correlates of prolactin levels in women.
Section snippets
In vitro and animal evidence for a role of prolactin in breast carcinogenesis
Substantial information indicates that prolactin has multiple effects on normal and malignant breast cells. It is well-established that prolactin has a mitogenic action in breast cells [2]. In breast cancer cell lines, exogenous prolactin administration increased cell proliferation [14], [16], [20], and in one study overrode irradiation-induced growth arrest [20]. Similarly, in a breast cancer cell line induced to endogenously produce high levels of prolactin, proliferation was increased 1.5
Epidemiologic evidence that prolactin is involved in breast carcinogenesis
Epidemiologic data on the relation between prolactin and breast cancer are more limited than in vitro and animal data. Several case reports have suggested that prolactinomas, a condition associated with extremely high prolactin levels, may be associated with breast cancer development [43], [44], [45], [46]. A small cohort study of 98 women with prolactinomas did not observe an association with breast cancer, however, average follow-up was only 3.6 years [47]. One limitation of studying breast
Correlates of serum and plasma prolactin levels
It is important to evaluate how lifestyle and other risk factors are associated with circulating prolactin levels, to better understand whether prolactin may be a mechanism through which certain risk factors alter breast cancer risk and to provide information about ways in which women might lower their prolactin levels through lifestyle changes. Although a detailed discussion of this area is beyond the scope of the current review, we briefly summarize the literature to date. The most
Conclusions
In summary, experimental evidence and accumulating epidemiologic data strongly suggest that prolactin is involved in the etiology of at least some breast tumors in both premenopausal and postmenopausal women. Further follow-up in existing prospective cohort studies is needed to confirm and better define the relationship between prolactin and breast cancer risk, especially in premenopausal women. Given the potential interplay between prolactin and estrogens it will be important to examine the
Acknowledgements
Support for this project was from NIH grants P01 CA87969 and CA49449.
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