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Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor Beta in breast cancer.

ABSTRACT: We previously identified cystatin C (CystC) as a novel antagonist of transforming growth factor beta (TGF-beta) signaling in normal and malignant cells. However, whether the anti-TGF-beta activities of CystC can be translated to preclinical animal models of breast cancer growth and metastasis remains unproven. Assessing the preclinical efficacy of CystC was accomplished using metastatic 4T1 breast cancer cells, whose oncogenic responses to TGF-beta were inhibited both in vitro and in vivo. Indeed, we observed CystC to prevent TGF-beta from stimulating the growth and pulmonary metastasis of 4T1 tumors in mice in part by reducing the extent of Smad2, p38 mitogen-activated protein kinase, and extracellular signal-regulated kinase 1/2 phosphorylation present in 4T1 tumors. We also found CystC to significantly antagonize angiogenesis in developing 4T1 tumors, suggesting a novel role for CystC in uncoupling TGF-beta signaling in endothelial cells (ECs). Accordingly, CystC dramatically reduced murine and human EC responsiveness to TGF-beta, including their ability to regulate the expression of 1) TGF-beta signaling components, 2) inhibitor of differentiation (ID) family members, and 3) matrix metalloproteinases and their inhibitors (TIMPs) and to undergo cell invasion and angiogenic sprouting stimulated by TGF-beta. Importantly, CystC prevented TGF-beta from stimulating vessel development in Matrigel plugs implanted into genetically normal mice. Collectively, our findings provide the first preclinical evidence that CystC is efficacious in preventing breast cancer progression and angiogenesis stimulated by the oncogenic TGF-beta signaling system and suggest that CystC-based chemotherapeutics possesses translational efficacy to one day treat and improve the clinical course of late-stage breast cancers.

SUBMITTER: Tian M

PROVIDER: S-EPMC2730134 | biostudies-literature | 2009 Aug

REPOSITORIES: biostudies-literature

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Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor Beta in breast cancer.

Tian Maozhen M Schiemann William P WP

Translational oncology 20090801 3

We previously identified cystatin C (CystC) as a novel antagonist of transforming growth factor beta (TGF-beta) signaling in normal and malignant cells. However, whether the anti-TGF-beta activities of CystC can be translated to preclinical animal models of breast cancer growth and metastasis remains unproven. Assessing the preclinical efficacy of CystC was accomplished using metastatic 4T1 breast cancer cells, whose oncogenic responses to TGF-beta were inhibited both in vitro and in vivo. Indee ...[more]

PMID: 19701502

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Project description:IntroductionEpithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) facilitate breast cancer (BC) metastasis; however, stable molecular changes that result as a consequence of these processes remain poorly defined. Therefore, with the hope of targeting unique aspects of metastatic tumor outgrowth, we sought to identify molecular markers that could identify tumor cells that had completed the EMT:MET cycle.MethodsAn in vivo reporter system for epithelial cadherin (E-cad) expression was used to quantify its regulation in metastatic BC cells during primary and metastatic tumor growth. Exogenous addition of transforming growth factor β1 (TGF-β1) was used to induce EMT in an in situ model of BC. Microarray analysis was employed to examine gene expression changes in cells chronically treated with and withdrawn from TGF-β1, thus completing one full EMT:MET cycle. Changes in fibroblast growth factor receptor type 1 (FGFR1) isoform expression were validated using PCR analyses of patient-derived tumor tissues versus matched normal tissues. FGFR1 gene expression was manipulated using short hairpin RNA depletion and cDNA rescue. Preclinical pharmacological inhibition of FGFR kinase was employed using the orally available compound BGJ-398.ResultsMetastatic BC cells undergo spontaneous downregulation of E-cad during primary tumor growth, and its expression subsequently returns following initiation of metastatic outgrowth. Exogenous exposure to TGF-β1 was sufficient to drive the metastasis of an otherwise in situ model of BC and was similarly associated with a depletion and return of E-cad expression during metastatic progression. BC cells treated and withdrawn from TGF-β stably upregulate a truncated FGFR1-β splice variant that lacks the outermost extracellular immunoglobulin domain. Identification of this FGFR1 splice variant was verified in metastatic human BC cell lines and patient-derived tumor samples. Expression of FGFR1-β was also dominant in a model of metastatic outgrowth where depletion of FGFR1 and pharmacologic inhibition of FGFR kinase activity both inhibited pulmonary tumor outgrowth. Highlighting the dichotomous nature of FGFR splice variants and recombinant expression of full-length FGFR1-α also blocked pulmonary tumor outgrowth.ConclusionThe results of our study strongly suggest that FGFR1-β is required for the pulmonary outgrowth of metastatic BC. Moreover, FGFR1 isoform expression can be used as a predictive biomarker for therapeutic application of its kinase inhibitors.

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Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor Beta in breast cancer.

Publications

Preclinical efficacy of cystatin C to target the oncogenic activity of transforming growth factor Beta in breast cancer.

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