To investigate the role of β-catenin in mammary gland development and neoplasia, we expressed a stabilized, transcriptionally active form of β-catenin lacking the NH2-terminal 89 amino acids (ΔN89β-catenin) under the control of the mouse mammary tumor virus long terminal repeat. Our results show that ΔN89β-catenin induces precocious lobuloalveolar development and differentiation in the mammary glands of both male and female mice. Virgin ΔN89β-catenin mammary glands resemble those found in wild-type (wt) pregnant mice and inappropriately express cyclin D1 mRNA. In contrast to wt mammary glands, which resume a virgin appearance after cessation of lactation, transgenic mammary glands involute to a midpregnant status. All transgenic females develop multiple aggressive adenocarcinomas early in life. Surprisingly, the ΔN89β-catenin phenotype differs from those elicited by overexpression of Wnt genes in this gland. In particular, ΔN89β-catenin has no effect on ductal side branching. This suggests that Wnt induction of ductal branching involves additional downstream effectors or modulators.
β-Catenin plays important roles in mammary development and tumorigenesis through its functions in cell adhesion, signal transduction and regulation of cell-context-specific gene expression. Studies in mice have highlighted the critical role of β-catenin signaling for stem cell biology at multiple stages of mammary development. Deregulated β-catenin signaling disturbs stem and progenitor cell dynamics and induces mammary tumors in mice. Recent data showing deregulated β-catenin signaling in metaplastic and basal-type tumors suggest a similar link to reactivated developmental pathways and human breast cancer. The present review will discuss β-catenin as a central transducer of numerous signaling pathways and its role in mammary development and breast cancer.
In a recent issue of Breast Cancer Research, investigators from the Serra laboratory describe a novel mechanism of transforming growth factor (TGF)-β tumor suppression. Previously, the authors discovered that stromal TGF-β signaled through Wnt5a to restrain pubertal ductal elongation and branching. Here, they show that inhibition of stromal TGF-β signaling or Wnt5a loss leads to increased β-catenin transcriptional activity and reduced latency in mammary tumor models, with tumors displaying a higher proportion of progenitor cell markers. These findings reveal a novel intersection of two tumor suppressors with a potent oncogenic pathway and highlight the need for further study on the role played by canonical Wnt signaling in breast cancer susceptibility and subtype.Rosa Serra has made important contributions to our understanding of the role played by transforming growth factor (TGF)-β in breast throughout her career, and in a recent issue of Breast Cancer Research she describes a novel mechanism of TGF-β tumor suppression [1]. Early work utilizing inducible dominant-negative type II receptors (metallothioneinlike promoter-TGF-β dominant negative type II receptor [MT-DNIIR] and mouse mammary tumor virus long terminal repeat [MMTV]-DNIIR) to suppress TGF-β signaling demonstrated that, despite its name, the function of TGF-β within the mammary gland is one of cell type-specific restraint. TGF-β signaling within stromal cells restrains lateral branching, and TGF-β signaling within luminal epithelial cells restrains alveolar development [2,3]. Recently, the investigators from the Serra laboratory conducted a microarray analysis to identify genes that were affected by DNIIR expression, and in so doing they discovered a link between TGF-β and Wnt5a, which is a member of the Wnt family of secreted morphogens. They then elegantly combined genetics with transplantation approaches to establish that Wnt5a is essential for TGF-β-mediated restraint of ductal outgrowth and branching [4]. Multiple Wnts are expressed in breast, and their signaling through canonical (β-catenin mediated) and noncanonical pathways is critical throughout mammary development [5]. Although deregulated canonical signaling induces murine mammary tumors and is implicated in human breast cancers, Wnt5a appears to act as a breast tumor suppressor [6,7]. This activity may be related to its propensity to signal through noncanonical pathways that, in many settings, antagonize canonical Wnt signaling [7].Having demonstrated the physiologic function of the TGF-β/ Wnt5a pathway in the mammary gland, the authors next focused on its role in tumor suppression [1]. When crossed to MMTV-PyVmT or MMTV-neu transgenic models, MT-DNIIR and Wnt5a -/-mice developed tumors with increased proliferation and earlier onset. Wnt5a levels were decreased in DNIIR tumors, supporting the notion that TGF-β regulates Wnt5a [1]. Whether Wnt5a expression can rescue the loss of tumor suppression exhibited by MT-DNIIR mice remains to be demonstrated. Nonetheless, the possibility tha...
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