Aberrant activation of the mTOR pathway is a characteristic alteration in triple-negative breast cancer, but the mTOR pathway inhibitor everolimus is not effective for the triple-negative breast cancer (TNBC) patients. Presently, we showed that the activation of ERK pathway was an important mechanism of resistance to everolimus in TNBC cells in this study. SHOC2, a key protein mediating the Ras-Raf-ERK pathway, could act as a scaffolding protein to facilitate the activation of the pathway by mediating the interaction of key components of the pathway. Our results showed that everolimus activated the Raf-ERK pathway by promoting the interaction between SHOC2 and c-Raf and that knockdown of SHOC2 significantly inhibited the Raf-ERK pathway induced by everolimus. We further demonstrated that SHOC2 expression levels were closely related to the sensitivity of TNBC cells to everolimus and that interference with SHOC2 expression in combination with everolimus had significant effects on the cell cycle progression and apoptosis in vitro experiments. Western blotting analysis showed that cell cycle regulators and apoptosis-related proteins were significantly altered by the combination treatment. Xenograft model also demonstrated that knockdown of SHOC2 significantly increased the sensitivity of tumor to everolimus in nude mice. In conclusion, our study showed that SHOC2 is a key factor in regulating the sensitivity of TNBC cells to everolimus and that combined therapy may be a more effective therapeutic approach for TNBC patients.
Keywords: Raf-ERK pathway; SHOC2; TNBC; drug resistance; everolimus.