Liu T.,Emory University |
Yacoub R.,Emory University |
Taliaferro-Smith L.D.,Emory University |
Sun S.-Y.,Emory University |
And 8 more authors.
Molecular Cancer Therapeutics | Year: 2011
Triple-negative breast cancers, which lack estrogen receptor, progesterone receptor, and HER2/neu overexpression, account for approximately 15% of breast cancers, but occur more commonly in African Americans. The poor survival outcomes seen with triple-negative breast cancers patients are, in part, due to a lack of therapeutic targets. Epidermal growth factor receptor (EGFR) is overexpressed in 50% of triple-negative breast cancers, but EGFR inhibitors have not been effective in patients with metastatic breast cancers. However, mTOR inhibition has been shown to reverse resistance to EGFR inhibitors. We examined the combination effects of mTOR inhibition with EGFR inhibition in triple-negative breast cancer in vitro and in vivo. The combination of EGFR inhibition by using lapatinib and mTOR inhibition with rapamycin resulted in significantly greater cytotoxicity than the single agents alone and these effectswere synergistic in vitro. The combination of rapamycin and lapatinib significantly decreased growth of triple-negative breast cancers in vivo compared with either agent alone. EGFR inhibition abrogated the expression of rapamycin-induced activated Akt in triple-negative breast cancer cells in vitro. The combination of EGFR and mTOR inhibition resulted in increased apoptosis in some, but not all, triple-negative cell lines, and these apoptotic effects correlated with a decrease in activated eukaryotic translation initiation factor (eIF4E). These results suggest that mTOR inhibitors could sensitize a subset of triple-negative breast cancers to EGFR inhibitors. Given the paucity of effective targeted agents in triple-negative breast cancers, these results warrant further evaluation. ©2011 American Association for Cancer Research.
Taliaferro-Smith L.,Emory University |
Oberlick E.,Emory University |
Oberlick E.,Harvard University |
Liu T.,Emory University |
And 12 more authors.
Oncotarget | Year: 2015
Triple negative breast cancer (TNBC) is a highly metastatic disease that currently lacks effective prevention and treatment strategies. The insulin-like growth factor 1 receptor (IGF1R) and focal adhesion kinase (FAK) signaling pathways function in numerous developmental processes, and alterations in both are linked with a number of common pathological diseases. Overexpression of IGF1R and FAK are closely associated with metastatic breast tumors. The present study investigated the interrelationship between IGF1R and FAK signaling in regulating the malignant properties of TNBC cells. Using small hairpin RNA (shRNA)-mediated IGF1R silencing methods, we showed that IGF1R is essential for sustaining mesenchymal morphologies of TNBC cells and modulates the expression of EMT-related markers. We further showed that IGF1R overexpression promotes migratory and invasive behaviors of TNBC cell lines. Most importantly, IGF1R-driven migration and invasion is predominantly mediated by FAK activation and can be suppressed using pharmacological inhibitors of FAK. Our findings in TNBC cells demonstrate a novel role of the IGF1R/FAK signaling pathway in regulating critical processes involved in the metastatic cascade. These results may improve the current understanding of the basic molecular mechanisms of TNBC metastasis and provide a strong rationale for co-targeting of IGF1R and FAK as therapy for mesenchymal TNBCs.
Habtes I.,Georgia Cancer Center for Excellence |
Habtes I.,Stony Brook University Medical Center |
Friedman D.,Emory University |
Raskind-Hood C.,Emory University |
And 12 more authors.
Cancer | Year: 2013
Background: In November 2009, the US Preventive Service Task Force (USPSTF) published updated breast cancer screening guidelines. This marked a change from the 2002 recommendations and a significant divergence from the American Cancer Society (ACS) guidelines. In the current study, the potential effect of using the revised 2009 USPSTF guidelines on patient disease stage and survival were evaluated and compared with those actually observed and to predicted under ACS recommendations. Methods: A retrospective chart review was performed for 84 patients who were diagnosed with stage I through III breast cancer at Grady Memorial Hospital during 2008. Previously published tumor volume doubling times were used to model an equation that would estimate tumor sizes. For each patient, a disease stage at diagnosis was predicted, and outcomes were modeled as though the patient had been screened according to the recommended versions of the ACS and USPSTF guidelines. Patient survival rates were then estimated based on prognostic data according to disease stage. Results: The average age of patients in the study was 55 years, and 85% were African American. The USPSTF guidelines predicted later stages at diagnosis (14% stage I, 73% stage II), whereas the ACS guidelines predicted earlier stages (47% stage I, 53% stage II). Conclusions: A large stage migration was predicted, indicating significantly earlier diagnosis, when the ACS-recommended screening guidelines were followed. The authors concluded that practitioners should understand how race and/or socioeconomic factors increase the risk of breast cancer and should be encouraged to prioritize discussions regarding the benefits and risks of annual mammographic screening, especially among women who have a potentially greater risk of developing breast cancer at a younger age. Cancer 2013. © 2012 American Cancer Society.