Latent Bone Metastasis in Breast Cancer Tied to Src-Dependent Survival Signals

Abstract

Metastasis may arise years after removal of a primary tumor. The mechanisms allowing latent disseminated cancer cells to survive are unknown. We report that a gene-expression signature of c-Src activation is associated with late-onset bone metastasis in breast cancer. This link is independent of hormone receptor status or breast cancer subtype. In breast cancer cells, c-Src is dispensable for homing to the bones or lungs critical for the survival and outgrowth of these cells in the bone marrow. c-Src mediates AKT regulation and cancer cell survival responses to CXCL12 and TRAIL, factors which are distinctively expressed in the bone metastasis microenvironment. Breast cancer cells that lodge in the bone marrow succumb in this environment when deprived of c-Src activity.

Targeting Cell Spreading: A Method of Sensitizing Metastatic Tumor Cells to TRAIL-Induced Apoptosis

“…Targeting Src family kinases, essential for relaying survival signals from the focal adhesion complex, led to a decrease in downstream paxillin phosphorylation, and sensitized these cells to TRAIL-induced apoptosis. This supports findings by Zhang and colleagues that Src signaling can aid metastatic breast cancer cell resistance to TRAIL signaling in the bone microenvironment (23).…”

“…These kinases form another signaling hub downstream of integrins and talin. Increased Src activity in cancers has been linked to anoikis resistance, and increased propensity for metastasis (22)(23)(24). These oncogenic kinases can signal to downstream pathways such as mitogen-activated protein kinase (MAPK), Akt, and many others, influencing adhesion, motility, invasion, proliferation, and survival (25,26).…”

Premetastatic milieu explained by TLR4 agonist-mediated homeostatic inflammation

“…24 Less than 1% of recruited tumor cells appear to achieve regrowth. How metastasizing tumor cells survive and start outgrowth in a given organ is still an unanswered question, but this event has recently been reported to be regulated by VEGFR1 in the lungs, 25 Src-mediated signaling of CXCL12 in bone, 26 and transcription factor HoxB9 and Lef1-dependent Wnt/Tcf signaling in brain and bone. 27 Even in RAGnull mice, normal breast cells can be recruited to the lungs without oncogene activation.…”

LB100, a small molecule inhibitor of PP2A with potent chemo- and radio-sensitizing potential

“…PP2A has been shown to dephosphorylate and therefore inhibit Src, a non-receptor tyrosine kinase that has been shown to mediate TRAIL resistance in breast cancer cells via activation of Akt pathway survival signaling. 102,103 Using the BT549 breast cancer cell line, Xu et al demonstrated that TRAIL signaling activated Src, which in turn phosphorylated caspase-8, initiating apoptosis. 104 Using immunoprecipitation, they found that TRAIL stimulation led to increased PP2A dephosphorylation of Src, abrogating Src-mediated activation of caspase-8.…”