Abstract

Breast cancer cells may release the p85 isoform of S6K1 to act in surrounding cells and promote tumor growth. Messaging by oncogenic kinase Cancer cells generate an environment amenable for their growth by signaling through various pathways to other cancer cells and nontransformed cells. Zhang et al. noticed that p85, the longest isoform of the growth-promoting kinase S6K1, had a six-arginine residue motif in its N terminus that was not present in shorter isoforms. This motif resembles a motif in the HIV TAT protein that enables it to be released from cells and enter surrounding cells. In cultured breast cancer or nontransformed cells, adding the p85 isoform of S6K1 to the medium enhanced the phosphorylation of S6K1 targets and behaviors characteristic of cancer cells, such as increased cell size and migration. Furthermore, injection of this S6K1 isoform into mice increased the growth and metastasis of xenografts formed by breast cancer cells. Because the S6K1 gene is amplified in some breast cancers, an antibody that targets this longer isoform may attenuate tumor growth and metastasis. Cancer cells can remodel surrounding microenvironments to facilitate cell growth, invasion, and migration by secreting proteins that educate surrounding stromal cells. We report that p85S6K1, the longest isoform of S6K (ribosomal protein S6 kinase), but not the shorter isoform p70S6K1 or p56S6K2, was secreted from cancer cells through its HIV TAT-like, N-terminal six-arginine motif. The exogenously produced p85S6K1 protein entered cultured transformed and nontransformed cells to promote or confer malignant behaviors, leading to increased cell growth and migration. When injected into mice, the p85S6K1 protein enhanced the growth of xenografted breast cancer cells and lung metastasis. Hence, our findings reveal a role for p85S6K1 as a secreted oncogenic kinase and provide a mechanism by which cancer cells remodel their microenvironment by transforming the surrounding cells to drive tumorigenesis.