Wnt and mammary stem cells: hormones cannot fly wingless

Abstract

The mammary stem cell and its local microenvironment are central for the maintenance of proper tissue homeostasis during normal development. Defining the hierarchical organization of the epithelial subtypes in the mammary gland and the molecular pathways guiding their development has begun to provide a framework for understanding how cancer stem cells sustain the progression and heterogeneity of breast cancers. The Wnt pathway plays a fundamental role in multiple adult stem cells, as well as in orchestrating proper mammary gland development and maintenance. These processes are intricately guided by the influence of systemic hormones and local factors. Alterations in Wnt signaling can skew the homeostatic balance of the mammary epithelium to drive malignant progression; however, complexities of Wnt pathway components present a challenge in understanding their physiological function.

Figure 1. Wnt Signaling: A Basic View

Wnt signaling is broadly divided into ß-catenin-dependent and ß-catenin-independent pathways. The ß-catenin-dependent pathway is involved in the stabilization of ß-catenin by the dissociation of a destruction complex that normally phosphorylates and targets ß-catenin for degradation. These signals require Fzd receptors to recruit the LRP co-receptor. ß-catenin-independent pathways encompass a broad range of outputs, dictated by the receptor context and downstream signals chosen. The newly discovered receptor tyrosine kinases Ror and Ryk provide another level of Wnt regulation in addition to Fzd. Within the Wnt family, there are 19 individual Wnt genes along with 10 different Frizzled receptors, illustrating the complexity governing this pathway and the multitude of Wnt-receptor combinations. The secreted Wnt inhibitors, Sfrps and Wifs, can regulate signaling in the extracellular space by sequestering Wnts away from their receptors. Wnt/ß-catenin-independent pathways can antagonize the ß-catenin-dependent pathway, revealing that these pathways are far more integrated than originally thought.

Figure 2. Wnts as Paracrine Mediators

ERα/PR positive cells provide extrinsic cues to ERα/PR negative cells to allow them to proliferate (Ki67). In addition to known paracrine mediators of hormonal action in the mammary gland, such as amphiregulin downstream of estrogen (E-dependent) and RANKL downstream of progesterone (P-dependent), Wnt ligands represent candidate mediators of mammary development. Wnt4 is the best-characterized Wnt, known to facilitate progesterone actions. The role of other Wnts remains unclear. The biological output of secreted Wnts depends on the receptor repertoire of the receiving cell along with the given developmental context. Lrp5/6 resides in the basal cell layer and is a marker of MaSCs, indicating the presence of Wnt/ß-catenin-dependent signaling in this compartment. Secreted inhibitors like Sfrps and Wifs can also modulate Wnt signaling by sequestering Wnts from their receptors (not shown).