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Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis.

Zhang J, Li Y, Liu Q, Lu W, Bu G - Oncogene (2009)

Bottom Line: We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions.More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls.Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.

ABSTRACT
Although Wnt signaling activation is frequently observed in human breast cancer, mutations in genes encoding intracellular components of the Wnt signaling pathway are rare. We found that the expression of Wnt signaling co-receptor, LRP6, is upregulated in a subset of human breast cancer tissues and cell lines. To examine whether the overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions. The expression of several Wnt target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls. Several matrix metalloproteinases are upregulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.

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Mammary gland hyperplasia in MMTV-LRP6 mice. (a) Mammary glands from MMTV-LRP6 virgin mice or WT littermate controls (Founder 4 line) at 14 or 21 weeks of age were analyzed by whole mount staining. Inset: high magnification of a selected area. Note mammary hyperplasia in MMTV-LRP6 mice. Bar, 500 μm, inset, 400 μm. (b) Quantification of terminal end buds (TEBs) from WT and MMTV-LRP6 mice (Founder 4, n=4) at 14 or 21 weeks of age. Error bars represent SD. *P<0.05 indicates a significant difference compared to mammary glands from WT littermate controls.
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Figure 3: Mammary gland hyperplasia in MMTV-LRP6 mice. (a) Mammary glands from MMTV-LRP6 virgin mice or WT littermate controls (Founder 4 line) at 14 or 21 weeks of age were analyzed by whole mount staining. Inset: high magnification of a selected area. Note mammary hyperplasia in MMTV-LRP6 mice. Bar, 500 μm, inset, 400 μm. (b) Quantification of terminal end buds (TEBs) from WT and MMTV-LRP6 mice (Founder 4, n=4) at 14 or 21 weeks of age. Error bars represent SD. *P<0.05 indicates a significant difference compared to mammary glands from WT littermate controls.

Mentions: Whole mount preparations are a well-established method to identify early premalignant lesions of the mammary epithelium (Cardiff et al., 2000). Thus, we performed whole-mount staining of virgin glands to examine the ductal structure of mammary glands in MMTV-LRP6 transgenic mice and WT littermate controls. As shown in Figure 3a, examination of a mammary gland taken from a wild-type littermate control female mouse revealed a branching ductal structure typical of a virgin female. In contrast, inspection of the MMTV-LRP6 mammary gland revealed an unusual number of secondary and tertiary branches and small, spiculated side buds. Quantification of terminal end buds (TEBs) from mammary glands revealed that TEBs from MMTV-LRP6 virgin mice (Founder 4) at 14 weeks (n=4) and 21 weeks (n=4) of age are 3.3 and 6 folds higher, respectively, than those from WT littermate control glands (Figure 3b). Both the founder 1 and 4 lines displayed similar mammary epithelial abnormalities with the founder 4 line having more significant hyperplasia. Furthermore, histological sections of virgin glands showed more individual ducts lined with cuboidal epithelium in transgenic mammary glands than WT littermate control glands (Figures 2c, d). These findings indicate that overexpression of LRP6 in the mouse mammary gland is sufficient to induce mammary gland hyperplasia.


Wnt signaling activation and mammary gland hyperplasia in MMTV-LRP6 transgenic mice: implication for breast cancer tumorigenesis.

Zhang J, Li Y, Liu Q, Lu W, Bu G - Oncogene (2009)

Mammary gland hyperplasia in MMTV-LRP6 mice. (a) Mammary glands from MMTV-LRP6 virgin mice or WT littermate controls (Founder 4 line) at 14 or 21 weeks of age were analyzed by whole mount staining. Inset: high magnification of a selected area. Note mammary hyperplasia in MMTV-LRP6 mice. Bar, 500 μm, inset, 400 μm. (b) Quantification of terminal end buds (TEBs) from WT and MMTV-LRP6 mice (Founder 4, n=4) at 14 or 21 weeks of age. Error bars represent SD. *P<0.05 indicates a significant difference compared to mammary glands from WT littermate controls.
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Figure 3: Mammary gland hyperplasia in MMTV-LRP6 mice. (a) Mammary glands from MMTV-LRP6 virgin mice or WT littermate controls (Founder 4 line) at 14 or 21 weeks of age were analyzed by whole mount staining. Inset: high magnification of a selected area. Note mammary hyperplasia in MMTV-LRP6 mice. Bar, 500 μm, inset, 400 μm. (b) Quantification of terminal end buds (TEBs) from WT and MMTV-LRP6 mice (Founder 4, n=4) at 14 or 21 weeks of age. Error bars represent SD. *P<0.05 indicates a significant difference compared to mammary glands from WT littermate controls.
Mentions: Whole mount preparations are a well-established method to identify early premalignant lesions of the mammary epithelium (Cardiff et al., 2000). Thus, we performed whole-mount staining of virgin glands to examine the ductal structure of mammary glands in MMTV-LRP6 transgenic mice and WT littermate controls. As shown in Figure 3a, examination of a mammary gland taken from a wild-type littermate control female mouse revealed a branching ductal structure typical of a virgin female. In contrast, inspection of the MMTV-LRP6 mammary gland revealed an unusual number of secondary and tertiary branches and small, spiculated side buds. Quantification of terminal end buds (TEBs) from mammary glands revealed that TEBs from MMTV-LRP6 virgin mice (Founder 4) at 14 weeks (n=4) and 21 weeks (n=4) of age are 3.3 and 6 folds higher, respectively, than those from WT littermate control glands (Figure 3b). Both the founder 1 and 4 lines displayed similar mammary epithelial abnormalities with the founder 4 line having more significant hyperplasia. Furthermore, histological sections of virgin glands showed more individual ducts lined with cuboidal epithelium in transgenic mammary glands than WT littermate control glands (Figures 2c, d). These findings indicate that overexpression of LRP6 in the mouse mammary gland is sufficient to induce mammary gland hyperplasia.

Bottom Line: We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions.More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls.Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Washington University School of Medicine, St Louis, MO 63110, USA.

ABSTRACT
Although Wnt signaling activation is frequently observed in human breast cancer, mutations in genes encoding intracellular components of the Wnt signaling pathway are rare. We found that the expression of Wnt signaling co-receptor, LRP6, is upregulated in a subset of human breast cancer tissues and cell lines. To examine whether the overexpression of LRP6 in mammary epithelial cells is sufficient to activate Wnt signaling and promote cell proliferation, we generated transgenic mice overexpressing LRP6 in mammary epithelial cells driven by the mouse mammary tumor virus (MMTV) promoter. We found that mammary glands from MMTV-LRP6 mice exhibit significant Wnt activation evidenced by the translocation of beta-catenin from membrane to cytoplasmic/nuclear fractions. The expression of several Wnt target genes including Axin2, Cyclin D1 and c-Myc was also increased in MMTV-LRP6 mice. More importantly, mammary glands from virgin MMTV-LRP6 mice exhibit significant hyperplasia, a precursor to breast cancer, when compared with wild-type littermate controls. Several matrix metalloproteinases are upregulated in MMTV-LRP6 mice that could contribute to the hyperplasia phenotype. Our results suggest that Wnt signaling activation at the cell-surface receptor level can contribute to breast cancer tumorigenesis.

Show MeSH
Related in: MedlinePlus