Clinical Anatomy 00:000–000 (2012) REVIEW Anatomy of the Human Mammary Gland: Current Status of Knowledge 1,2 1 FOTEINI HASSIOTOU AND DONNA GEDDES * 1Hartmann Human Lactation Research Group, School of Chemistry and Biochemistry, Faculty of Science, The University of Western Australia, Crawley, Western Australia, Australia 2School of Anatomy, Physiology and Human Biology, Faculty of Science, The University of Western Australia, Crawley, Western Australia, Australia Mammary glands are unique to mammals, with the specific function of synthe- sizing, secreting, and delivering milk to the newborn. Given this function, it is only during a pregnancy/lactation cycle that the gland reaches a mature devel- opmental state via hormonal influences at the cellular level that effect drastic modifications in the micro- and macro-anatomy of the gland, resulting in remodeling of the gland into a milk-secretory organ. Pubertal and post-puber- tal development of the breast in females aids in preparing it to assume a func- tional state during pregnancy and lactation. Remarkably, this organ has the capacity to regress to a resting state upon cessation of lactation, and then undergo the same cycle of expansion and regression again in subsequent pregnancies during reproductive life. This plasticity suggests tight hormonal regulation, which is paramount for the normal function of the gland. This review presents the current status of knowledge of the normal macro- and micro-anatomy of the human mammary gland and the distinct changes it undergoes during the key developmental stages that characterize it, from em- bryonic life through to post-menopausal age. In addition, it discusses recent advances in our understanding of the normal function of the breast during lac- tation, with special reference to breastmilk, its composition, and how it can be utilized as a tool to advance knowledge on normal and aberrant breast devel- opment and function. Finally, anatomical and molecular traits associated with aberrant expansion of the breast are discussed to set the basis for future com- parisons that may illuminate the origin of breast cancer. Clin. Anat. Clin. Anat. 00:000–000, 2012. VC 2012 Wiley Periodicals, Inc. Key words: breast; mammary gland; anatomy; histology; stem cells; lactocytes; lactation; breast cancer INTRODUCTION Grant sponsors: Medela AG, Women and Infants Research The mammary gland is an organ unique to the Foundation. class Mammalia, with the specific function to synthe- *Correspondence to: Donna Geddes, Hartmann Human Lactation size, secrete, and deliver milk to the newborn upon Research Group, School of Chemistry and Biochemistry, Faculty of demand for its optimal nourishment, protection, Life and Physical Sciences, The University of Western Australia, 35 and development (Medina, 1996). Milks from differ- Stirling Highway, Crawley, Western Australia 6009, Australia. ent mammalian species vary in composition and are E-mail: [email protected] uniquely appropriate for the species for which the Received 2 July 2012; Accepted 16 August 2012 milk was synthesized. In humans, the life cycle of Published online in Wiley Online Library (wileyonlinelibrary.com). the female mammary gland is epitomized by drastic DOI 10.1002/ca.22165 VC 2012 Wiley Periodicals, Inc. 2 Hassiotou and Geddes changes in composition, architecture, and functional- DEVELOPMENT OF THE BREAST ity, mediated by marked changes in gene expres- sion, that characterize its physiological stages of de- Breast development during life follows a time velopment, all of which are aimed at allowing it to course of distinct phases. Beginning with the forma- perform its function as a milk-producing organ with tion of the mammary crest and subsequent primitive the birth of the infant. The key mammary develop- mammary buds during embryonic life, it continues mental stages include fetal growth, infant (pre- with minimal growth during infancy followed by a pubertal) growth, pubertal expansion, pregnancy- rapid growth phase at puberty in the female. Breast and lactation-associated remodeling, and post-lacta- development culminates during the pregnancy and tional and post-menopausal involution (Russo, 2004; lactation cycle (PLC) when the mammary gland Geddes, 2007). A sound knowledge of the develop- undergoes complete remodeling, maturating into a ment, anatomy, physiology, and regulation of the functional milk-secretory organ. Regression of PLC- breast is integral in the understanding of both the induced growth is initiated as weaning is commenced normal biology and function of this organ and its be- and is completed after involution when the breast nign or malignant pathologies and their successful regresses to a resting state. Remarkably, the PLC- treatment. induced mammary growth and subsequent involution Unlike most other organs of the body, which de- can be repeated at multiple pregnancies during the velop to a relatively mature state during embryonic reproductive life of a female. The cycle is completed life, the mammary gland reaches a mature functional with a further phase of involution post-menopause. state only during the pregnancy-lactation cycle (PLC) Full development of the breast during lactation is in the adult female. Therefore, this is the most im- critical to provide the appropriate volume and com- portant developmental stage of the breast when it is position of breastmilk for the growth, protection, and characterized by a very high metabolic demand, development of the infant. Further, it has been requiring about 25% of daily maternal energy intake shown that the PLC is protective against the develop- during lactation to produce milk (Hartmann, 2007). ment of breast cancer in the long term (Key et al., Human breastmilk has a unique biochemical and cel- 2001), particularly when it occurs before the age of lular composition, providing the infant with optimal 30 and with an interval of less than 14 years nutritional, protective, and developmental factors. between menarche and the first pregnancy. Multi- Due to this, the American Academy of Pediatrics parity confers slightly more protection; however, the (AAP, 2005) and the World Health Organisation effect is not as great as that of the first pregnancy (Russo, 2011). The above strongly suggest that (WHO) recommend breastfeeding (or the provision pregnancy and lactation induce permanent breast of mother’s own milk) for all infants, including high changes through which they exert a protective, risk and premature infants. Despite this, few women, yet still not well understood, effect against breast especially in developed countries, reach current rec- malignancy. ommendations for breastfeeding duration, which state exclusive breastfeeding to six months postpar- tum, with breastfeeding to continue up to two years Fetal Development or beyond. This situation suggests inadequate sup- Embryonic development of the breast is initiated port of the mother-infant dyad (term and preterm) by six weeks of gestation from a thickened ectoder- to achieve and maintain a successful lactation, mal ridge extending from the groin to the axilla on demonstrating a clear need to bridge scientific inves- the anterior surface of the embryo (milk line). The tigation of breast function and development of evi- entire ridge apart from the pectoral region (second dence-based medical treatment. to sixth rib) regresses to form the mammary gland. In addition to pathologies associated with suc- Supernumerary glands may develop at any location cessful lactation, breast cancer is another devastat- along the ectodermal ridge presenting as either ing pathology of the mammary gland, with current mammary glands or accessory nipples in 2–6% of statistics reporting it as the most frequent cancer women (Vorherr, 1974; Schmidt, 1998; Russo, and cancer-related cause of death in women world- 2004). wide (AIHW, 2010). Despite considerable scientific Between week 7 and 8 of gestation (embryo 10–11 effort into elucidating the primary cause of breast mm), the mammary parenchyma invades the stroma cancer, the differing responses to therapy and char- forming an elevated portion termed the mammary acteristics of its various subtypes (Perou et al., crest. A basement membrane separates the invading 2000) together with the lack of basic understanding ectodermal cells from the underlying mesoderm. of the physiology of the breast have hindered the de- Between 10 and 12 weeks gestation (embryo 30–68 velopment of appropriate preventative guidelines mm), mammary epithelial buds form, a phase that and treatment options for these patients. This review marks the commencement of distinct differentiation summarizes the current knowledge of the normal patterns. At this stage, subtle differences can be seen anatomy of the human breast and the distinct between males and females, such as the female ovoid changes it undergoes during the key developmental versus male spherical budding shape, and the female stages that characterize it. In addition, anatomical smaller bud volume. The smooth musculature of the and molecular traits associated with aberrant expan- areola and nipple are formed between 12 and 16 sion of the breast are discussed to set the basis for weeks. The appearance of the mammary buds does future comparisons that may illuminate the origin of not change significantly until weeks 13–20, when a breast cancer. depression is formed at the surface of the buds and A Review of the Anatomy of the Female Breast 3 proliferation of distinct epithelial progenitor popula- Puberty tions results in secondary