{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T00:24:05Z","timestamp":1790468645599,"version":"4.1.0"},"reference-count":58,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2012,9,20]],"date-time":"2012-09-20T00:00:00Z","timestamp":1348099200000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"},{"start":{"date-parts":[[2012,9,20]],"date-time":"2012-09-20T00:00:00Z","timestamp":1348099200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/2.0\/"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Breast Cancer Res"],"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n                        <jats:title>Introduction<\/jats:title>\n                        <jats:p>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\u03b2)-mediated breast cancer cell migration and invasion.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Methods<\/jats:title>\n                        <jats:p>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 SUM1315MO<jats:sub>2<\/jats:sub> were treated with 5 ng\/ml TGF\u03b2 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\u03b2 transcriptional activity was measured by a TGF\u03b2\/Smad reporter construct (CAGA12-luc) using luciferase assay. q-PCR was used for assessing TGF\u03b2 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\u03b2\/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.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Results<\/jats:title>\n                        <jats:p>We found p21 expression to correlate with poor overall and distant metastasis free survival in breast cancer patients. Furthermore, using xenograft animal models and <jats:italic>in vitro<\/jats:italic> 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\u03b2. p21 and p\/CAF regulates TGF\u03b2-mediated transcription of pro-metastatic genes by controlling Smad3 acetylation, DNA binding and transcriptional activity. In addition, we found that active TGF\u03b2\/Smad signaling correlates with high p21 and p\/CAF expression levels and lymph node involvement using tissue microarrays from breast cancer patients.<\/jats:p>\n                     <\/jats:sec><jats:sec>\n                        <jats:title>Conclusions<\/jats:title>\n                        <jats:p>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.<\/jats:p>\n                     <\/jats:sec>","DOI":"10.1186\/bcr3322","type":"journal-article","created":{"date-parts":[[2012,9,20]],"date-time":"2012-09-20T16:14:08Z","timestamp":1348157648000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":47,"title":["A novel function for p21Cip1 and acetyltransferase p\/CAF as critical transcriptional regulators of TGF\u03b2-mediated 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