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The Mammary Glands of Macaques1 Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA Correspondence: J. Mark Cline, DVM, PhD, DACVP, Professor of Pathology/Comparative Medicine, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157-1040, USA. Phone: (336) 716-1564; fax: (336) 716-1515; e-mail:jmcline{at}wfubmc.edu.
This review describes the normal biology and physiology of the mammary gland in macaques, including the typical histologic appearance across the life span (development, reproductive maturity, lactation, and senescence). The molecular events regulating breast morphogenesis are described, as well as systemic and local hormonal regulators of mammary gland proliferation, differentiation, and function. Similarities and differences to the human breast are described. Regulatory events are illuminated by discussion of genetically modified mouse models. Tissue response markers, including immunohistochemical markers of proliferation and other hormonally induced changes and studies to date, regarding the effects of exogenous hormones, are briefly summarized. In general, estrogens stimulate progesterone receptor expression and proliferation in the mammary gland, and combinations of estrogens and progestogens cause greater proliferation than estrogens alone. Evaluation of novel chemical agents in macaques requires careful evaluation of age and hormonal context to avoid the confounding effects of mammary gland development, past reproductive history, and other influences on mammary gland morphology. The expression of proliferation markers and progesterone receptors may be used as biomarkers to measure chemically induced hormonal effects. Competing Interests: This article was sponsored by Covance Inc. and Schering-Plough. The authors did not declare any other competing interests.
Key Words: primate pathology • mammary gland • estrogen • progesterone • proliferation • receptors • development Abbreviations: CEE, conjugated equine estrogens • GH, growth hormone • IGF, insulin-like growth factor • MPA, medroxyprogesterone acetate • NMGA, nomegestrol acetate • NETA, norethindrone acetate • Laso, lasofoxifene • Tam, tamoxifen • Ral, raloxifene • SERM 393 and 379, investigative selective estrogen receptor modulators
Toxicologic pathology of the mammary gland is primarily concerned with proliferative lesions, particularly neoplasms. This reflects the concern caused by the high incidence of mammary gland cancers in the human population; in the United States, breast cancer is the most common malignancy among women (Jemal et al. 2008). Major risk factors for breast cancer among women include age, nulliparity, or late first full-term pregnancy; the use of estrogen-progestogen hormone therapy after menopause; alcohol consumption; obesity after menopause; and family history (Evans and Howell 2007; Santen et al. 2007). Oral contraceptive use is associated with a slight increase in breast-cancer risk for current users that dissipates within a decade after cessation of use (Casey, Cerhan, and Pruthi 2008). Postmenopausal hormone therapy increases breast-cancer risk by approximately 50%, and that risk is clearest for combined estrogen-progestogen exposure (Collins, Blake, and Crosignani 2005). Higher circulating androgens are associated with higher breast-cancer risk in premenopausal women (Eliassen et al. 2006). Thus, careful evaluation of the mammary glands is most important in the evaluation of drug or chemical agents that mimic sex steroids; relevant effects may be estrogenic, progestogenic, androgenic, or mediated by a novel receptor interaction or indirect mechanism. Effects of drugs and chemicals on the mammary glands change dramatically across the life span. Chemically induced mammary carcinomas in rodents are most readily induced by treatment during the period of maximal mammary gland growth, around the time of puberty (Russo and Russo 1996). There is epidemiologic evidence from studies of women treated for Hodgkin’s disease during puberty that a similar period of sensitivity exists for human beings (Clemons, Loijens, and Goss 2000). The corresponding period of developmental sensitivity in macaques has been identified, and there are dramatic differences in the morphology and responsiveness of the mammary gland spanning the age of animals commonly used for toxicologic assessments (Wood, Hester, and Cline 2007). The appropriate use of nonhuman primates in studies of the mammary gland requires knowledge of the normal biology, hormonal responsiveness, and developmental context.
Macaques have two pectoral mammary glands. The nonlactating mammary glands are more flattened than those of nonlactating human females (Figure 1), but the histologic appearance is nearly identical. In macaques, as in women, the bulk of the glandular tissue lies above and lateral to the nipple, extending to the axilla. Primate breast tissues are easily studied at the sub-gross level by whole mount techniques (Figure 1; Cameron and Faulkin 1974; Speert 1948). The adult gland consists of a branching ductal system and terminal ductal lobular units consisting of a terminal intralobular duct and surrounding alveoli, invested with myoepithelium. There is substantial individual variation in the amount and distribution of glandular tissue among individual adult animals, due both to individual variation in development and to past reproductive history. In the nonlactating breast, approximately 5% of the organ is occupied by glandular epithelial tissue, with the remaining 95% consisting of fat, fibrous connective tissue, vascular, and nervous supply; these proportions are similar to those reported for women (Cline, Register, and Clarkson 2002). There are five to seven lactiferous ducts exiting each nipple, with varying degrees of communication between the corresponding ductal and lobular units, and occasional small clusters of glandular tissue in the nipple. The mammary gland of male cynomolgus monkeys is similar to that of females but much less developed, consisting of a small nipple and a rudimentary ductal and lobular system roughly 5 mm in diameter (Perry et al. 2007; Speert 1948).
During lactation, the breast becomes enlarged and more prominent, and in older animals, the breast tissue may become pendulous. A thin but distinct mammary fat pad is present, with a slightly firmer texture and less yellow color than the adjacent subcutaneous fat; this distinction may be obscured in obese animals. Innervation of the gland is similar to that of the human, consisting of sensory nerves of the nipple, major lactiferous ducts, and some terminal ductal lobular units. Innervation is nearly absent in lactating tissue distant from the nipple (MacPherson and Montagna 1974). The cytokeratin profile of the macaque mammary gland is similar to that of the human and differs from that of rodents and other species (Tsubura et al. 1991). The nonlactating macaque mammary gland differs somewhat from the human gland in that there are more often fat droplets within secretory epithelial cells, even in the quiescent gland (Figure 3). The basis for this subtle difference in breast morphology is not yet understood; macaques and humans have nearly identical reproductive physiology and milk composition (Jenness 1979; Lonnerdal et al. 1984) and lactate for a similar developmental period of their offspring (Buss 1971).
Growth and differentiation of the breast is dependent on ovarian and local production and activation of steroid hormones, the growth hormone (GH) or insulin-like growth factor (IGF) system, and secretory stimuli including prolactin and placental lactogen (Hennighausen and Robinson 2005). Few of these regulatory processes have been thoroughly studied in the breast of macaques; where information is lacking, comparative data from humans and other animal models have been provided.
Estrogens, Progestogens, and Androgens Studies of mice with targeted disruption of critical receptors are instructive regarding the role of sex steroids in breast development. Estrogen receptor (ER) alpha knockout mice show only rudimentary mammary gland development (Feng et al. 2007; Mueller et al. 2002), whereas ER beta knockout mice have relatively normal mammary glands (Forster et al. 2002). Progesterone receptor knockout mice have a profound defect in ductal side-branching and lobular development (Lydon et al. 1996). Mice lacking the androgen receptor also have somewhat impaired mammary gland development (Shiina et al. 2006). Interestingly, tissue-recombinant studies have shown that in mice stromal, but not epithelial, sex steroid receptors are required for mammary growth in this species (Cunha et al. 1997). The critical role of estrogens and progestogens in breast development and growth in macaques has been demonstrated by anatomic and biomarker studies during development (Wood, Hester, and Cline 2007), during the reproductive years (Stute et al. 2004), and after menopause (Cline 2007). Major findings in macaques are described in subsequent sections of this article.
GH/IGF Axis
Prolactin
Placental Lactogen (Somatomammotropin)
Intratissue Hormone Production
Estrogen exposure of the breast tissue is high in utero during breast morphogenesis. After birth, estrogen exposure declines until early puberty, when follicular development occurs for some months prior to ovulation, thus providing an estrogen-alone phase in which longitudinal ductal growth is pronounced and, to a lesser extent, lobular development begins (Wood, Hester, and Cline 2007). With the beginning of regular ovulation the breast is exposed to cyclic patterns of estrogens and progesterone, leading to further lobular development and stromal expansion. Hormonal exposure during pregnancy brings to bear a unique pattern of placentally derived factors at high circulating concentrations including estriol, chorionic gonadotropin, placental lactogen, and progesterone, resulting in full functional differentiation of the breast. Thus, hormonal signals are not only qualitative and quantitative but also time sensitive.
Fetal/Neonatal Development
Puberty
The extensive lobular development occurring during puberty in primates is distinct from the relatively limited lobular development occurring in nulliparous rodents. Juvenile macaques that have just begun to menstruate in some cases have mammary glands that are widely populated by well-differentiated, densely branched lobuloalveolar units of type 1 and 2 using the schema of Russo (Russo et al. 2000; Wood, Hester, and Cline 2007). Because the mammary gland of macaques grows so rapidly and invasively, care must be taken to avoid erroneously interpreting normal mammary gland development as hyperplasia or neoplasia, and the morphology of the breast must be considered in the context of the animal’s stage of reproductive development. Furthermore, there is a high degree of individual variation in the pace of breast development, making animal-to-animal comparisons difficult, if not impossible, during this period. Pubertal development of mammary tissues in male macaques is not well described; however, transient glandular development (gynecomastia) has been noted (Figure 6; J. Vidal, personal communication). Transient gynecomastia occurs in more than 50% of normal adolescent boys. The incidence of this change and the degree to which it may resemble breast developmental changes seen in human males (Lazala and Saenger 2002) or normal mammary glandular development seen in male rats (Cardy 1991) remain unknown.
Adult Breast
The effect of the menstrual cycle on proliferation in the breast is controversial; in the human breast, some investigators have found greater proliferation in the progesterone-dominated luteal phase of the cycle (Meyer 1977), whereas others have shown more proliferation in the estrogen-dominated follicular phase (Vogel et al. 1981). We have shown in macaques that cycle-related changes are small (less than a 6% difference in proportions of proliferating cells between luteal and follicular phases) and that there are compartmental differences in cellular proliferation in the macaque; ductal tissues proliferate more during the luteal phase, while lobuloalveolar tissues epithelium had higher proliferation during the late follicular phase (Stute et al. 2004). We also found that precise timing altered the result; when we compared the early follicular phase (day 5) to the mid-luteal phase, proliferative changes in both ducts and lobular epithelium were greater during the luteal phase (Wood, Appt, et al. 2006). Seasonal changes in the mammary gland have not been explored; thus, although some species of macaques such as the rhesus have distinctly seasonal reproductive patterns (Walker, Gordon, and Wilson 1983), no seasonal differences in hormonal responsiveness of the breast have been described. Cynomolgus macaques, in contrast to rhesus macaques, are not seasonal breeders (Dukelow, Grauwiler, and Brüggemann 1979).
Lactation Postlactational involution of the breast in macaques is not well described, but parous animals examined months to years after the last lactation have breast tissue similar to that of nulliparous animals. Although there is not sufficient data currently to state that there is a persistent breast-cancer-protective effect of lactation in macaques, such an effect is likely given the many similarities to humans.
Senescence
The effects of estrogens, progestogens, and a variety of novel agents on the breast of macaques has been the subject of many original papers and reviews from our laboratory, and much careful and interesting work by other investigators. A detailed discussion of this entire body of work would be redundant with two recently published reviews from our group (Cline 2007; Cline and Wood 2005). However, some specific patterns of effect are noteworthy and are summarized in Table 1. In general, estrogens (estradiol, conjugated equine estrogens, ethinyl estradiol, and others) stimulate the breast to proliferate and induce expression of progesterone receptors and other "classic" estrogenic markers such as trefoil factor 1 (TFF1, formerly known as PS2; Wood, Register, et al. 2007). A standard hormone replacement dose of estradiol is a more potent agonist than the standard dose of conjugated estrogens (Wood et al. 2008). Progestogens alone in ovariectomized animals have little measurable effect on the breast, aside from down-regulation of estrogen and progesterone receptors (Cline et al. 1998). The combination of estrogens and progestogens in the breast induces a greater proliferative response than do estrogens alone (Cline, Register, and Clarkson 2002; Cline et al. 1996, 1998; Wood, Register, et al. 2007), and in this regard, the macaque model corresponds to findings in women from the Women’s Health Initiative, in which combined estrogens (conjugated equine estrogens) plus progestogen (medroxyprogesterone acetate) treatment increased breast-cancer risk to a greater degree than did estrogens alone (Anderson et al. 2006). The addition of a progestogen also reduces expression of estrogen-responsive markers such as progesterone receptor and TFF1. Some synthetic progestogens, such as medroxyprogesterone acetate, may be more stimulatory than micronized progesterone (Wood, Register, et al. 2007) or alternative progestoges, such as norethindrone acetate (Suparto et al. 2003). Use of intravaginal administration of progestogens does not reduce the response of the breast to progestogen (Wood, Sitruk-Ware, et al. 2007). Dietary isoflavone phytoestrogens show little to no evidence of stimulatory effects on the macaque breast but, at supradietary doses, may antagonize the proliferative response to co-administered estradiol (Wood, Appt, et al. 2006; Wood, Kaplan, et al. 2006; Wood et al. 2006). The effects of androgens on the breast are currently unclear; Dimitrikakis et al. (2003) showed acute down-regulation of estrogen-induced proliferation by androgen co-administration, but human-observation studies indicate that higher endogenous androgens are associated with higher breast-cancer risk (Hankinson and Eliassen 2007). Selective estrogens such as raloxifene, lasofoxifene, and other novel agents have generally produced no effect on biomarkers in the breast (Sikoski et al. 2007), although, notably, the archetypal selective estrogen, tamoxifen, induces progesterone receptor (Cline et al. 1998) and, in one study, induced proliferation (Zhou et al. 2000) in the macaque breast.
In general, we have found that the number of animals required to detect statistically significant differences in qualitative histopathologic findings in the mammary gland is higher than the typically very low number of animals used in toxicology screening. Therefore, to reduce the numbers of animals used, we have adopted a biomarker approach (Cline et al. 1996, 1998; Cline, Register, and Clarkson 2002) as well as novel study designs such as crossover designs or pretreatment biopsy (Wood, Register, et al. 2006; Wood, Sitruk-Ware, et al. 2007) to reduce the effects of interindividual variability. We strongly recommend that any study involving assessment of the mammary gland should be performed in postpubertal animals.
Mammary gland development and hormonal responses in macaques are complex issues and show a high degree of similarity to the human breast, particularly with respect to their responses to hormonally active pharmacologic agents. Careful consideration of developmental stage, reproductive history, and hormonal context is necessary in the evaluation of breast changes in macaques. The high degree of interindividual differences in macaques may require novel strategies for evaluation of hormonal effects—for example, the use of pretreatment biopsy or the use of hormone-response biomarkers.
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Toxicologic Pathology, Vol. 36, No. 7 Suppl,
130S-141S (2008)
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Abstract
Introduction
