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

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.

miR302a inhibits the proliferation of esophageal cancer cells through the MAPK and PI3K/Akt signaling pathways

“…Therefore, miR302a may have targeted p-ERK1/2 and p-Akt through the MAPK and PI3K signaling pathways, respectively, and this may be its primary contribution to the inhibition of cell proliferation in TE-10 and ECA109 cells. Consistent with previous results, in the present study, the phosphorylation levels of Akt and ERK1/2 were significantly decreased in the miR302a mimics group (P<0.05), and increased in the miR302a inhibitor group (P<0.01) (23)(24)(25)(26). Furthermore, total Akt and ERK1/2 expression levels were also determined by western blot analysis in TE-10 and ECA109 cells, and overexpression of miR302a did not markedly differ between groups.…”

HSF1: Primary Factor in Molecular Chaperone Expression and a Major Contributor to Cancer Morbidity

“…HSF1 phosphorylation on S326 involved the kinase mTOR and led to an increase in nuclear β-catenin, a powerful inducer of stem cell proliferation. Knockdown of either HSF1 or mTORC1 abolished the tumor-initiating potential of human mammary carcinoma cells as indicated by a reduced capacity to form tumor spheroids in vitro [59], consistent with the study by Carpenter et al, who also reported reduced tumor spheroid formation under conditions of HSF1 inhibition [108]. Hsf1 was also shown to be an important factor for the emergence of an EMT phenotype in experimental tumor cells driven by the Neu oncogene or TGF-β treatment [63], as well as through control of the EMT regulator Slug downstream of HRG and HER2 [109].…”

Molecular Chaperones in Cancer Stem Cells: Determinants of Stemness and Potential Targets for Antitumor Therapy

“…In a breast cancer model, it was shown how one of the key players in the CSC phenotype formation, β-catenin, is regulated by HSF1 in a phosphorylation-dependent manner: The activating phosphorylation of HSF1 at serine 326 led to HSF1-mediated involvement of the RNA-binding protein HuR (human antigen R), which controls β-catenin mRNA translation [169]. Later, the significance of HSF1 phosphorylation at serine 326 for breast CSCs was confirmed by Carpenter et al, who revealed that the Akt-HSF1 signaling axis is responsible for the metastatic potential and self-renewal of breast CSCs [170]. Similarly, the activating phosphorylation of HSF1 at serine 326 was shown to be critical for the maintenance of gynecologic CSCs, although the researchers explained the effect of the HSF1 activation-triggered induction of HSP27 [171].…”

“…In another study, KRIBB11, a small molecule inhibitor of HSF1, was shown to kill breast CSCs with synergistic cytotoxicity if combined with MK-2206, an inhibitor of Akt [170].…”