S6K1 promotes invasiveness of breast cancer cells in a model of metastasis of triple-negative breast cancer.

Breast cancer is the second-leading cause of oncology-related death in US women. Of all invasive breast cancers, patients with tumors lacking expression of the estrogen and progesterone hormone receptors and overexpression of human epidermal growth factor receptor 2 have the poorest clinical prognosis. These referred to as triple-negative breast cancer (TNBC) represent an aggressive form of disease that is marked by early-onset metastasis, high tumor recurrence rate, and low overall survival during the first three years post-diagnosis. In this report, we discuss a novel model of early-onset TNBC metastasis to bone and lungs, derived from MDA-MB-231 cells. Breast cancer cells injected intravenously produced rapid, osteolytic metastases in long bones and spines of athymic nude mice, with concurrent metastasis to lungs, liver, and soft tissues. From the bone metastases, we developed a highly metastatic luciferase-tagged cell line variant named MDA-231-LUC Met. In this report, we demonstrate that the Akt/mTOR/S6K1 axis is hyperactivated in these cells, leading to a dramatic increase in phosphorylation of S6 ribosomal protein at Ser235/236. Lastly, we provide evidence that inhibition of the furthest downstream kinase in the mTOR pathway, S6K1, with a highly specific inhibitor PF-4708671 inhibits cell migration, and thus may provide a potent anti-metastatic adjuvant therapy approach.