Hormonal and local control of mammary branching morphogenesis

Abstract

Unlike other branched organs, the mammary gland undergoes most of its branching during adolescent rather than embryonic development. Its morphogenesis begins in utero, pauses between birth and puberty, and resumes in response to ovarian estrogens to form an open ductal tree that eventually fills the entire mammary fat pad of the young female adult. Importantly, this "open" architecture leaves room during pregnancy for the organ to develop milk-producing alveoli like leaves on otherwise bare branches. Thereafter, the ducts serve to deliver the milk that is produced throughout lactation. The hormonal cues that elicit these various phases of mammary development utilize local signaling cascades and reciprocal stromal-epithelial interactions to orchestrate the tissue reorganization, differentiation and specific activities that define each phase. Fortunately, the mammary gland is rather amenable to experimental inquiry and, as a result, we have a fair, although incomplete, understanding of the mechanisms that control its development. This review discusses our current sense and understanding of those mechanisms as they pertain to mammary branching, with the caveat that many more aspects are still waiting to be solved.

Fig. 1

Murine terminal end bud (TEB) and duct morphology. (A) High-magnification carmine alum-stained whole mount of a TEB that has recently bifurcated to form two new primary ducts. Two new secondary side-branches are also present along the trailing duct (open arrowhead), as is an area of increased cellularity that may represent a nascent lateral bud (closed arrowhead). Increased stromal cellularity is apparent around the bifurcating TEB. Scale bar: 200 µm. (B) Hematoxylin and eosin-stained section of a bifurcating TEB with an early lateral side-branch (closed arrowhead). Scale bar: 100 µm. (Image courtesy of A.J. Ewald, UCSF) (C) Schematic diagram depicting the major features of a bifurcating TEB. Notable features include the considerable proliferative activity (mitoses) within the TEBs, the single layer of TEB cap cells and multilayered pre-luminal body cells, the characteristic presence of a fibroblast-and collagen-rich stromal collar surrounding the neck of the bifurcating TEB, and its conspicuous absence beyond the invading distal cap of each new TEB. An increased number of macrophages and eosinophils is also shown. Although there is no evidence that normal ductal cells ever cross the basal lamina, thinning of the basement membrane (dashed lines) at the leading edge of the invading ducts may reflect partial enzymatic degradation and/or incomplete de novo synthesis of the basal lamina.

Fig. 2

Provisional model depicting some of the key endocrine and paracrine pathways involved in mammary branching morphogenesis. Solid arrows indicate interactions that influence mammary branching, whereas hashed lines indicate putative interconnections between known signaling cascades or indirect interactions for which signaling intermediates (e.g., mitogen-activated protein kinase) have not yet been determined.