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Ectodomain shedding of T?RIII is required for T?RIII-mediated suppression of TGF-? signaling and breast cancer migration and invasion.

ABSTRACT: The type III transforming growth factor ? (TGF-?) receptor (T?RIII), also known as betaglycan, is the most abundantly expressed TGF-? receptor. T?RIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. T?RIII binds TGF-? ligands, with membrane-bound T?RIII presenting ligand to enhance TGF-? signaling. However, T?RIII can also undergo ectodomain shedding, releasing soluble T?RIII, which binds and sequesters ligand to inhibit downstream signaling. To investigate the relative contributions of soluble and membrane-bound T?RIII on TGF-? signaling and breast cancer biology, we defined T?RIII mutants with impaired (?Shed-T?RIII) or enhanced ectodomain shedding (SS-T?RIII). Inhibiting ectodomain shedding of T?RIII increased TGF-? responsiveness and abrogated T?RIII's ability to inhibit breast cancer cell migration and invasion. Conversely, expressing SS-T?RIII, which increased soluble T?RIII production, decreased TGF-? signaling and increased T?RIII-mediated inhibition of breast cancer cell migration and invasion. Of importance, SS-T?RIII-mediated increases in soluble T?RIII production also reduced breast cancer metastasis in vivo. Taken together, these studies suggest that the ratio of soluble T?RIII to membrane-bound T?RIII is an important determinant for regulation of T?RIII- and TGF-?-mediated signaling and biology.

SUBMITTER: Elderbroom JL

PROVIDER: S-EPMC4142606 | biostudies-literature | 2014 Aug

REPOSITORIES: biostudies-literature

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Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.

Elderbroom Jennifer L JL Huang Jennifer J JJ Gatza Catherine E CE Chen Jian J How Tam T Starr Mark M Nixon Andrew B AB Blobe Gerard C GC

Molecular biology of the cell 20140625 16

The type III transforming growth factor β (TGF-β) receptor (TβRIII), also known as betaglycan, is the most abundantly expressed TGF-β receptor. TβRIII suppresses breast cancer progression by inhibiting migration, invasion, metastasis, and angiogenesis. TβRIII binds TGF-β ligands, with membrane-bound TβRIII presenting ligand to enhance TGF-β signaling. However, TβRIII can also undergo ectodomain shedding, releasing soluble TβRIII, which binds and sequesters ligand to inhibit downstream signaling. ...[more]

PMID: 24966170

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Project description:Tumor cell migration and invasion are critical initiation steps in the process of breast cancer metastasis, the primary cause of breast cancer morbidity and death. Here we investigated the role of p21Cip1 (p21), a member of the core cell cycle machinery, in transforming growth factor-beta (TGF?)-mediated breast cancer cell migration and invasion.A mammary fat pad xenograft mouse model was used to assess the mammary tumor growth and local invasion. The triple negative human breast cancer cell lines MDA-MB231 and its sub-progenies SCP2 and SCP25, SUM159PT, SUM149PT, SUM229PE and SUM1315MO2 were treated with 5 ng/ml TGF? and the protein expression levels were measured by Western blot. Cell migration and invasion were examined using the scratch/wound healing and Transwell assay. TGF? transcriptional activity was measured by a TGF?/Smad reporter construct (CAGA12-luc) using luciferase assay. q-PCR was used for assessing TGF? downstream target genes. The interactions among p21, p/CAF and Smad3 were performed by co-immunoprecipitation. In addition, Smad3 on DNA binding ability was measured by DNA immunoprecipitation using biotinylated Smad binding element DNA probes. Finally, the association among active TGF?/Smad signaling, p21 and p/CAF with lymph node metastasis was examined by immunohistochemistry in tissue microarray containing 50 invasive ductal breast tumors, 25 of which are lymph node positive.We found p21 expression to correlate with poor overall and distant metastasis free survival in breast cancer patients. Furthermore, using xenograft animal models and in vitro studies, we found p21 to be essential for tumor cell invasion. The invasive effects of p21 were found to correlate with Smad3, and p/CAF interaction downstream of TGF?. p21 and p/CAF regulates TGF?-mediated transcription of pro-metastatic genes by controlling Smad3 acetylation, DNA binding and transcriptional activity. In addition, we found that active TGF?/Smad signaling correlates with high p21 and p/CAF expression levels and lymph node involvement using tissue microarrays from breast cancer patients.Together these results highlight an important role for p21 and p/CAF in promoting breast cancer cell migration and invasion at the transcriptional level and may open new avenues for breast cancer therapy.

Dataset Information

Ectodomain shedding of T?RIII is required for T?RIII-mediated suppression of TGF-? signaling and breast cancer migration and invasion.

Publications

Ectodomain shedding of TβRIII is required for TβRIII-mediated suppression of TGF-β signaling and breast cancer migration and invasion.

Similar Datasets

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