Mammary gland development requires syndecan-1 to create a β-catenin/TCF-responsive mammary epithelial subpopulation

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 Sdc1À/À mammary epithelial cells (mecs) to the intracellular, activated Wnt signal transducer, DNb-catenin, was assayed both in vitro and in vivo, to test whether b-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 Sdc1À/À mecs and in stimulated cells responding to Wnt1 or DNb-catenin. Tumor development in response to DNb-catenin was also significantly delayed on a Sdc1À/À background. Furthermore, the average b-catenin/TCF transactivation per cell was normal in Sdc1À/À mec cultures, but the number of responsive cells was reduced by 50%. Sdc1À/À 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 Sdc1À/À 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 b-catenin/TCF-responsive tumor precursor cells in mouse mammary gland.

Juvenile syndecan-1 null mice are protected from carcinogen-induced tumor development

“…As mammary ductal development is impaired in these mice (Liu et al, 2003), we considered the possibility that altered lactation could slow postnatal growth. We therefore tested embryo size in pregnant Sdc1 þ /À BALB/c females (mated to Sdc1 þ /À males).…”

“…However, Sdc1À/À mice do not phenocopy any of the mouse models that have been engineered for loss of function of these signaling pathways. We have previously shown that heparan sulfate is conjugated to other core proteins in Sdc1À/À mice (Liu et al, 2003), suggesting that this compensatory process could be responsible for the effective rescue of HS-mediated functions. Sdc1 has been variously implicated in processes that impinge upon tumor development, and has been shown to either promote or inhibit tumor development in xenograft or culture models (Bernfield et al, 1999;Whitelock and Iozzo, 2005).…”

“…The fact that mice with a constitutive mutation of Sdc1 show such subtle alterations of phenotype appears to contradict the substantial roles ascribed to this molecule in cultured cells. For Sdc1À/À mammary epithelial cells, we have shown that heparan sulfate function is rescued by compensatory conjugation of heparan sulfate side chains to other core proteins (Liu et al, 2003). The phenotype of these mice is therefore likely to be dominated by functions of the core protein that cannot be substituted by generic cell surface heparan sulfate core proteins (Kramer and Yost, 2003).…”

Regulation of matrix biology by matrix metalloproteinases

“…Although other metalloproteinases may participate in this process, MT-MMPs have been reported to cleave syndecan-1 and this shedding may affect cell motility [36]. Recent reports indicate that syndecan-1 plays an important role in mammary gland development and tumor progression via its influence on the Wnt signaling pathway [37,38]. Syndecan-1 may act as a co-receptor for important cell surface molecules or ECM components and thus play a role in regulating intracellular signaling pathways.…”

Differential Gene Expression Analysis Reveals Activation of Growth Promoting Signaling Pathways by Tenascin-C

“…Experiments by Liu et al (26) suggest that increased DKK1 expression can reduce ␤-catenin-specific transactivation. Taken together with our results, which show that DKK1 expression lowers ␤-catenin expression, we deduce that decreased expression of DKK1 in T98G cells by tenascin-C leads to the induction of the Wnt signaling pathway.…”