Identification of a Stat3-Dependent Transcription Regulatory Network Involved in Metastatic Progression

Abstract

High levels of activated Stat3 are often found in human breast cancers and can correlate with poor patient outcome. We employed an activated ErbB2 mouse model of breast cancer to investigate the in vivo role of Stat3 in mammary tumor progression and found that Stat3 does not alter mammary tumor initiation but dramatically affects metastatic progression. Four-fold fewer animals exhibited lung metastases in the absence of Stat3 and a 12-fold reduction in the number of lung lesions was observed in animals bearing Stat3-null tumors when compared with the wild-type cohort. The decreased malignancy in Stat3-deficient tumors is attributed to a reduction in both angiogenic and inflammatory responses associated with a Stat3-dependent transcriptional cascade involving CCAAT/enhancer binding protein D. [Cancer Res 2009;69(17):6823-30]

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer

“…Thus the coupled expression of ErbB2 and Cre recombinase precludes the possibility of obtaining ErbB2-expressing Crenegative 'escapee' populations that could possibly contribute to the tumor. Indeed, we successfully showed that this approach results in complete ablation of targeted allele in NIC mice harboring either Stat3 or ShcA conditional alleles (Ursini- Siegel et al, 2008;Ranger et al, 2009).…”

Transcription factor regulatory networks in mammary epithelial development and tumorigenesis

“…Recently published data suggests that the pro-inflammatory functions of STAT3 during mammary gland involution may also have a critical role in mammary tumor progression. In this work, mammary epithelial disruption of STAT3 in transgenic mice expressing the ErbB2 oncogene provide compelling evidence that a STAT3-dependent pro-inflammatory program is required for the metastatic phase of tumor progression (Ranger et al, 2009). Although mammary tumor onset was not affected by ablation of STAT3, the resulting tumors rarely metastasized to the lung (Ranger et al, 2009).…”

“…In this work, mammary epithelial disruption of STAT3 in transgenic mice expressing the ErbB2 oncogene provide compelling evidence that a STAT3-dependent pro-inflammatory program is required for the metastatic phase of tumor progression (Ranger et al, 2009). Although mammary tumor onset was not affected by ablation of STAT3, the resulting tumors rarely metastasized to the lung (Ranger et al, 2009). Remarkably, analyses of gene expression profile of these STAT3-deficient ErbB2 tumors revealed that the acute inflammatory response was dramatically impaired because of the reduced expression of C/EBPd, OSMR, SAA1 and SAA2.…”

“…Accumulated genetic lesions within a breast cancer cell will have an impact on how these networks interact and will thus ultimately shape the tumor phenotype. In addition to epithelial cell-autonomous consequences, activation of these transcription networks can also have an impact on other cell types within the tumor microenvironment and thereby influence their capacity to metastasize (Ranger et al, 2009). The future elucidation of the complex relationship between the normal and pathological outputs of these networks may provide important therapeutic insights into the treatment of breast cancer.…”

Oncogenes and Tumor Suppressor Genes

“…For example, disruption of Stat3 in mammary epithelium can have a profound impact on ErbB2-driven tumor progression. Although ErbB2 can induce tumors in the absence of Stat3, these tumors fail to metastasize (Ranger et al 2009). Examination of the gene expression profile of Stat3-deficient tumors revealed that they failed to induce the expression of a number of Stat3 target genes involved in inflammation (Ranger et al 2009).…”