Signalling pathways implicated in early mammary gland morphogenesis and breast cancer

Abstract

Specification of mammary epithelial cell fate occurs during embryogenesis as cells aggregate to form the mammary anlage. Within the embryonic mammary bud, a population of epithelial cells exists that will subsequently proliferate to form a ductal tree filling the stromal compartment, and which can produce milk upon terminal differentiation after birth. Subsequently, these structures can be remodelled and returned to a basal state after weaning before regenerating in future pregnancies. The plasticity of the mammary epithelial cell, and its responsiveness to hormone receptors, facilitates this amazing biological feat, but aberrant signalling may also result in unintended consequences in the form of frequent malignancies. Reflecting this intimate connection, a considerable number of signalling pathways have been implicated in both mammary gland morphogenesis and carcinogenesis.

Figure 1. Mammary Anlagen

(A) Mammary anlagen 3 and 4 are visible at E10.75/E11.0 (38–40 somites) in histological sagittal sections of mouse embryos stained with hematoxylin. FL, forelimb bud; HL, hindlimb bud; MLM, mammary line mesenchyme; NT, neural tube (B) Higher magnification of mammary region from (A). Anlagen 3 and 4 at higher magnification.

Figure 2. Histological Sections of Mammary Anlage 4 Stained with Hematoxylin

(A) Late E10/E11 as cells initially aggregate into elliptical shape. (B) E11.5 epidermal thickening. (C) E12.0 at hillock stage. (D) E13.0 at spherical bud stage. (E) E14.5 at light bulb stage.

Figure 3. Expression of the Major Regulators of Mammary Anlage Formation

60-μm vibratome cross sections through the site where anlage 3 will subsequently form. Fgf10 and Tbx3 expression is observed in the dermamyotome along the mammary line of E10.5/32 somite stage B6 embryos. These expression patterns are maintained until the anlage becomes morphologically distinct. Nrg3 is broadly expressed in the lateral plate mesoderm adjacent to the somite of E10.75 37 somite stage B6 embryos underlying the future site of anlage 3. Wnt expression (visualized using the BAT-GAL line of Wnt reporter mice [124]) is observed in the somite and by the future mammary anlage 3 site of E10.75 37 somite stage embryo. Both epithelial (arrowheads) and mesenchymal Wnt expression is observed along the mammary line. The expression along the presumptive mammary line is boxed.

Figure 4. Model for Mammary Anlage Formation and Cell Fate Determination

This model is based on functional studies as well as the expression patterns of Fgf10, Nrg3, Tbx3, and Wnts in the presumptive mammary region between E10 and E11 when initiating processes are likely to occur. Unknown axial cues are generated so that mammary anlagen arise at specific locations along the anterior–posterior, dorsal–ventral axis. Other factors are involved, and genetic requirements are likely to vary for each of the five pairs of anlagen. For example, Fgf10 is not required for the initial formation of anlagen 4, so this simplified model applies to anlagen 1, 2, 3, and 5.