Oncotarget

Research Papers:

Combined inhibition of AKT and HSF1 suppresses breast cancer stem cells and tumor growth

Richard L. Carpenter, Sherona Sirkisoon, Dongqin Zhu, Tadas Rimkus, Alexandria Harrison, Ashley Anderson, Ivy Paw, Shadi Qasem, Fei Xing, Yin Liu, Michael Chan, Linda Metheny-Barlow, Boris C. Pasche, Waldemar Debinski, Kounosuke Watabe and Hui-Wen Lo _

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Oncotarget. 2017; 8:73947-73963. https://doi.org/10.18632/oncotarget.18166

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Abstract

Richard L. Carpenter1, Sherona Sirkisoon1, Dongqin Zhu1, Tadas Rimkus1, Alexandria Harrison1, Ashley Anderson1, Ivy Paw1, Shadi Qasem2,4, Fei Xing1,4, Yin Liu1, Michael Chan3,4, Linda Metheny-Barlow3,4,5, Boris C. Pasche1,4, Waldemar Debinski1,3,4,5, Kounosuke Watabe1,4 and Hui-Wen Lo1,4,5

1Department of Cancer Biology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA

2Department of Pathology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA

3Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA

4Department of Radiation Oncology, Wake Forest University School of Medicine, Winston Salem, NC 27157, USA

5Brain Tumor Center of Excellence, 1 Medical Center Drive, Winston Salem, NC 27157, USA

Correspondence to:

Hui-Wen Lo, email: hlo@wakehealth.edu

Keywords: HSF1, AKT, MK-2206, KRIBB11, stem cells

Received: March 07, 2017     Accepted: May 11, 2017     Published: May 22, 2017

ABSTRACT

Breast cancer is the most common cancer in women and the second leading cause of cancer deaths in women. Over 90% of breast cancer deaths are attributable to metastasis. Our lab has recently reported that AKT activates heat shock factor 1 (HSF1), leading to epithelial-to-mesenchymal transition in HER2-positive breast cancer. However, it is unknown whether the AKT-HSF1 pathway plays an important role in other breast cancer subtypes, breast cancer stem cells, or breast cancer growth and metastasis. Herein, we showed AKT and HSF1 to be frequently co-activated in breast cancer cell lines and specimens across different subtypes. Activated AKT (S473) and HSF1 (S326) are strongly associated with shortened time to metastasis. Inhibition of the AKT-HSF1 signaling axis using small molecule inhibitors, HSF1 knockdown or the dominant-negative HSF1 mutant (S326A) reduced the growth of metastatic breast cancer cells and breast cancer stem cells. The combination of small molecule inhibitors targeting AKT (MK-2206) and HSF1 (KRIBB11) resulted in synergistic killing of breast cancer cells and breast cancer stem cells across different molecular subtypes. Using an orthotopic xenograft mouse model, we found that combined targeting of AKT and HSF1 to significantly reduce tumor growth, induce tumor apoptosis, delay time to metastasis, and prolong host survival. Taken together, our results indicate AKT-HSF1 signaling mediates breast cancer stem cells self-renewal, tumor growth and metastasis, and that dual targeting of AKT and HSF1 resulted in synergistic suppression of breast cancer progression thereby supporting future testing of AKT-HSF1 combination therapy for breast cancer patients.


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