STAT5调节STAT3及三阴性乳腺癌的侵袭性行为

Triple Negative Breast Cancer (TNBC) is an aggressive subtype of breast cancer that accounts for about 15-20% of cases and often has high rates of metastasis. Signal transducer and activator of transcription 3 (STAT3) is constitutively active and highly associated with TNBC. Alternatively, STAT5 expression is often lost or reduced in TNBC and metastasis. STAT5 activation in breast cancer is generally associated with more differentiated tumors and better response to therapies. Interestingly, breast tumors with concurrent activation of STAT3 and STAT5 generally have improved prognostic outlooks compared to tumors with activation of STAT3 alone, suggesting that STAT5 can attenuate some of the aggressive characteristics associated with STAT3 activity. Therefore, understanding how STAT5 can modulate these aggressive phenotypes associated with STAT3 could improve therapies for individuals with TNBC or metastatic breast cancer. STAT3 and STAT5 are latent transcription factors that reside in the cytoplasm. Upon phosphorylation of a specific tyrosine residue, these STATs can enter the nucleus and regulate transcription of target genes. To characterize STAT3 and STAT5 activity in breast tumor subtypes, activity scores were calculated for patients from the Cancer Genome Atlas. STAT3 activity was found to be highest in basal tumors, whereas STAT5 activity was lowest in basal tumors. Furthermore, epithelial to mesenchymal (EMT) scores were calculated for each patient using gene set variation analysis and STAT5 activity was negatively correlated with EMT. Additionally, relapse free survival was improved in patients with high levels of STAT5 and low levels of STAT3 in basal breast tumors. To determine if STAT5 directly modulated EMT and STAT3 in TNBC, a doxycycline-inducible constitutive STAT5 construct was introduced into the TNBC cell line, MDA-MB-231, which contains constitutively active STAT3. It was determined that constitutive STAT5 activation can reduce the viability of these cells. Moreover, preliminary results suggest that STAT5 can affect response to drug treatment and may modulate expression of certain genes involved in EMT. Lastly, in rare cases, breast cancer can metastasize to the peritoneal cavity. Using a mesothelial clearance assay adapted for breast cancer, we found that constitutive STAT5 activation in TNBC cells reduced mesothelial clearance, which is an important step in peritoneal metastasis. Moreover, activation of constitutive STAT5 and concurrent inhibition of STAT3 reduced mesothelial clearance with a greater effect compared to activation of STAT5 or inhibition of STAT3 alone. Therefore, activation of STAT5 can potentially reduce the aggressive behaviors of TNBC. These findings have potential implications in treating patients with TNBC and metastatic breast cancer.