Review of Mammary Gland Neoplasia in Nonhuman Primates

Abstract

A macaque model of breast cancer in humans has been in development over the past several years by Mark Cline and colleagues at North Carolina College of Veterinary Medicine. Recently the North Carolina group was able to characterize thirty-five mammary gland lesions ranging from ductal hyperplasia to carcinoma in situ and invasive ductlal carcinomas that have occurred in cynomolgus and rhesus macaques at various NIH sponsored primate research centers in the United States [1]. In this model they have demonstrated events similar to those described in human breast cancer, such as upregulation of proliferation markers in mammary duct epithelia, as well as alterations in estrogen and progesterone receptors, growth factor receptors, markers of cell death, and the development of morphologically preneoplastic changes. These workers estimated a lifetime incidence of 6% for mammary gland neoplasia in captive macaques and queried whether breast cancer is underreported in simian primates. They also highlight the morphologic and molecular similarities of breast cancer and humans and macaques. Although still a matter for debate, recent evidence based on mitochondrial DNA suggests humans and cercopithecine old world primates, which includes macaques [2], diverged from a common ancestor 25 million years before present time [3–5]. Based on this relative proximity in the evolutionary time scale, nonhuman primates provide an attractive model for humans because of similarities in anatomy and physiology [6– 8]. With regard to the female reproductive system some of these similarities include a unicornuate uterus, a menstrual cycle and pectoral lobulated ductal-alveolar mammary glands [9–11]. Mammary gland tissue is diffusely distributed in all directions of the subcutis over the pectoral and abdominal muscles, resulting in a barely perceptible enlargement even during lactation. The general architecture and innervation of ducts and glands is similar to the human. An average of 5 to 7 lactiferous ducts emerge at the tip of the nipple. Scattered between these ducts are longitudinally orientated bands of smooth muscle. The thick-walled ducts descend to the base of the nipple and abruptly dilate into a mildly tortuous thin-walled lactiferous sinus, which is fed by dozens of small ducts from the surrounding glandular tissue. In both rhesus monkeys and humans, nerve endings are found at the tip of the nipple, as well as surrounding thick-walled ducts of the nipple, some lactiferous sinuses and some small ducts. The supporting fibrous connective tissue of the mammary gland changes from loosely organized during immaturity to more densely packed swirls in the adult. Among the primate genera studied, extensive data on reproduction has been accumulated from macaques, mainly rhesus (Macaca mulatta) and cynomolgus (Macaca fasicularis) monkeys. Macaques, old world primates of the family Cercopithecidae constitute the largest group of nonhuman primates living in managed colonies. Rhesus monkeys attain menarche at 3 to 5 years old, have