Diverse and Active Roles for Adipocytes During Mammary Gland Growth and Function

Abstract

The mammary gland is unique in its requirement to develop in close association with a depot of adipose tissue that is commonly referred to as the mammary fat pad. As discussed throughout this issue, the mammary fat pad represents a complex stromal microenvironment that includes a variety of cell types. In this article we focus on adipocytes as local regulators of epithelial cell growth and their function during lactation. Several important considerations arise from such a discussion. There is a clear and close interrelationship between different stromal tissue types within the mammary fat pad and its adipocytes. Furthermore, these relationships are both stage- and species-dependent, although many questions remain unanswered regarding their roles in these different states. Several lines of evidence also suggest that adipocytes within the mammary fat pad may function differently from those in other fat depots. Finally, past and future technologies present a variety of opportunities to model these complexities in order to more precisely delineate the many potential functions of adipocytes within the mammary glands. A thorough understanding of the role for this cell type in the mammary glands could present numerous opportunities to modify both breast cancer risk and lactation performance.

Expression of NGF, BDNF and their high-affinity receptors in ovine mammary glands during development and lactation

“…This is consistent again with the role of the mammary fat pad and the loose intralobular stroma as source of paracrine and endocrine molecules (Sternlicht et al 2005;Wang et al 2008;Hovey and Aimo 2010), with the abundant cell proliferation occurring in the prepubertal period of mammary development and with the autocrine proliferative action of neurotrophins in breast cancer (Hondermarck 2012). In fact, NGF and BDNF may constitute an important local regulator of mammary gland development playing a central role in promoting survival of mammary cells via phosphatidylinositol 3-kinase (PI3K) and protein kinase B (AKT), as IGF1 does, or via mitogen-activated protein kinase (MEK1/2), like epidermal growth factor (EGF) through its ErbB receptor that is also a tyrosine kinase.…”

Essential Role for Zinc Transporter 2 (ZnT2)-mediated Zinc Transport in Mammary Gland Development and Function during Lactation

“…Consistent with effects of adipocyte zinc accumulation, we observed adipocyte hypertrophy in ZnT2-null mammary glands, which could indicate increased lipogenesis (59). Therefore, the loss of ZnT2 in adipocytes may mirror insulinlike effects on lipogenesis that stunt ductal growth (60) or may affect the synthesis or release of paracrine factors, such as adiponectin and collagen VI (61) from adipocytes that initiate epithelial/mesenchymal interaction and facilitate ductal expansion (55). Finally, macrophages are also important for mammary gland development, as they are recruited to the epithelial cells to support proliferation for ductal outgrowth (30,62) by supplying growth factors, cytokines, and chemokines (63) or by engulfing apoptotic cells that interfere with epithelial proliferation (64).…”

“…Moreover, prolactin stimulates leptin secretion from mammary adipose, which up-regulates expression of estrogen receptor ␣ and can negatively impact the maintenance of the secreting epithelium through inhibition of Stat signaling in MECs during lactation (76). Because we detected ZnT2 in adipocytes, it is possible that ZnT2-mediated zinc transport plays a role in lactation-induced lipolysis via lipoprotein lipase (55). The inability to clear triglycerides from adipocyte depots may partially underlie the lower level of milk fat observed in ZnT2-null mice.…”

“…Consequently, the loss of ZnT2 in these cells may also affect optimal development of the ductal tree. Adipocytes dictate the extent of which the glandular tissue develops into a functional branching network in the mammary gland (55) by secreting leptin and other endocrine factors that contribute to paracrine interactions with ductal epithelial cells (56); thus, enhanced adipocyte mass may affect these interactions. Moreover, zinc has insulin-like effects in adipocytes, stimulating lipogenesis and increasing fatty acid accumulation (57,58).…”

Gene expression differences in adipose tissue associated with breast tumorigenesis

“…Proliferating tumor cells require a source of energy to divide as well as lipids for membrane production. Lipolysis of adjacent adipocytes by mammary epithelial cells occurs during lactation 29 ; this may be coopted by tumor epithelial cells to provide tumors with a source of energy. 30 The role of adipose tissue as not only fuel for tumor growth, but also in recruiting macrophages and stimulating an inflammatory response, may contribute to the less favorable outcomes of obese breast cancer patients.…”