Abstract
Mice with a null mutation in the cell surface heparan sulfate (HS) proteoglycan, syndecan-1 (Sdc1), develop almost normally, but resist mammary tumor development in response to Wnt-1. Here, we test the hypothesis that Sdc1 promotes Wnt-1-induced tumor development by interacting with the Wnt cell surface signaling complex. Thus, the response of Sdc1−/− mammary epithelial cells (mecs) to the intracellular, activated Wnt signal transducer, ΔNβ-catenin, was assayed both in vitro and in vivo, to test whether β-catenin/TCF transactivation was Sdc1-independent. Surprisingly, we found that the expression of a canonical Wnt pathway reporter, TOP-FLASH, was reduced by 50% in both unstimulated Sdc1−/− mecs and in stimulated cells responding to Wnt1 or ΔNβ-catenin. Tumor development in response to ΔNβ-catenin was also significantly delayed on a Sdc1−/− background. Furthermore, the average β-catenin/TCF transactivation per cell was normal in Sdc1−/− mec cultures, but the number of responsive cells was reduced by 50%. Sdc1−/− mecs show compensatory changes that maintain the number of HS chains, hence these experiments cannot test the coreceptor activity of HS for Wnt signaling. We propose that TCF-dependent transactivational activity is suppressed in 50% of cells in Sdc1−/− glands, and conclude that the major effect of Sdc1 does not map to the activity of the Wnt signaling complex, but to another pathway to create or stabilize the β-catenin/TCF-responsive tumor precursor cells in mouse mammary gland.
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Abbreviations
- HS:
-
heparan sulfate
- HSPG:
-
heparan sulfate proteoglycan
- Sdc1:
-
syndecan-1
- wg:
-
wingless
- Fz:
-
frizzled receptor
- mecs:
-
mammary epithelial cells
- ΔNβcat:
-
[ΔN89]-β-catenin
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Acknowledgements
Thanks to Ann Wozniak for determination of genotypes of transgenic mice. Thanks to Kathy Schell, Pamela Whitney and Joan Batchelder at the University of Wisconsin Flow Cytometry for their expertise and hard work. Thanks also to Sarah Millar for giving us a dkk1 clone before publication. This work is supported by NIH Grant CA 90877-01, a grant from the American Cancer Society (IRG-58-011-43-01), the University of Wisconsin Cancer Center Support Grant (P30 CA14520), a training award for BL (T32 CA09135) and an award from the Howard Hughes Medical Institute Research Resources Program for Medical Schools.
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Liu, B., Kim, Y., Leatherberry, V. et al. Mammary gland development requires syndecan-1 to create a β-catenin/TCF-responsive mammary epithelial subpopulation. Oncogene 22, 9243–9253 (2003). https://doi.org/10.1038/sj.onc.1207217
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DOI: https://doi.org/10.1038/sj.onc.1207217
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