Side-branching in the mammary gland: the progesterone–Wnt connection

The mammary gland is a derivative of the ectoderm whose development begins in the embryo and progresses after birth. The major part of development occurs in the adolescent and adult animal. Hormones produced by the pituitary, the ovaries, the uterus, the placenta, and the mammary gland itself control this process. Over the past century, surgical, biological, and genetic tools have been used to gain insight into physiological and pathological processes in the mammary gland. Originally, endocrine ablation and reconstitution experiments provided a descriptive framework of the role of ovarian and pituitary hormones (Halban 1900; Nandi 1958). These experiments demonstrated a clear requirement for the ovarian steroids estrogen and progesterone for ductal growth and alveolar development (Topper and Freeman 1980). In prepubescent mice the gland consists of a small ductal tree that emanates from the nipple into the proximal part of the fatty stroma, the mammary fat pad (Fig. 1). Upon initiation of ovarian hormone secretion, the mammary epithelium enters an accelerated growth phase that leads to extension and branching of the ducts until they reach the limits of the fat pad. In response to changing levels of estrogens and progestins during each estrous cycle, alveolar buds are formed from the lateral walls of the ducts and lost again. At the onset of pregnancy extensive epithelial cell proliferation occurs, leading to formation of lobulo-alveolar structures and secretory epithelial differentiation. These morphogenetic and cellular responses are controlled by signaling cascades initiated by progesterone (Lydon et al. 1995), placental lactogens, and prolactin (Horseman et al. 1997; Ormandy et al. 1997).

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