Fig. 4: Hypothetical model illustrating the multiple actions of SL-145 on TNBC tumor growth and metastasis.

Our findings indicate that (i) SL-145 targets the C-terminal domain of HSP90 without induction of the heat shock response, and (ii) effectively induces apoptotic cell death in TNBC cells. (iii) SL-145 not only kills the rapidly proliferating cells that comprise the tumor bulk, but also effectively eradicates BCSC-like traits. (iv) SL-145 administration retards tumor growth and angiogenesis, and subsequently suppresses metastasis to the lungs and liver, concomitant with suppression of the STAT3 downstream factors cyclin D1, survivin, vimentin, and MMP-2/-9. (v) These phenomena are associated with an impediment of major HSP90 client oncoproteins including AKT, MEK/ERK, and JAK2/STAT3, as well as pluripotent transcription factors. Taken together, these findings support the notion that further investigation of the novel C-terminal HSP90 inhibitor SL-145 for the treatment of metastatic triple-negative breast cancers is warranted. [Heat shock response, HSR; Heat shock factor-1, HSF-1, Heat shock element, HSE].