Regulation of inflammatory breast cancer cell invasion through Akt1/PKBα phosphorylation of RhoC GTPase.
With a 42% and 18% 5- and 10-year respective disease-free survival rate, inflammatory breast cancer (IBC) is arguably the deadliest form of breast cancer. IBC invades the dermal lymphatic vessels of the skin overlying the breast and as a consequence nearly all women have lymph node involvement and ~1/3 have gross distant metastases at the time of diagnosis. One year after diagnosis ~90% of patients have detectable metastases, making IBC a paradigm for lymphovascular invasion. Understanding the underlying mechanisms of the IBC metastatic phenotype is essential for new therapies. Work from our laboratory and others show distinct molecular differences between IBC and non-IBCs (nIBCs). Previously we showed that RhoC GTPase is a metastatic switch responsible for the invasive phenotype of IBC. In this study we integrate observations made in IBC patients with in vitro analysis. We show that the PI3K/Akt signaling pathway is crucial in IBC invasion. Key molecules involved in cytoskeletal control and cell motility are specifically upregulated in IBC patients compared with stage and cell-type-of-origin matched nIBCs patients. Distinctively, RhoC GTPase is a substrate for Akt1 and its phosphorylation is absolutely essential for IBC cell invasion. Further our data show that Akt3, not Akt1 has a role in IBC cell survival. Together our data show a unique and targetable pathway for IBC invasion and survival.
Department of Biological Sciences, University of Delaware, Newark, DE 19716, USA.
Heather L
HL
Lehman
Steven J
SJ
Van Laere
Cynthia M
CM
van Golen
Peter B
PB
Vermeulen
Luc Y
LY
Dirix
Kenneth L
KL
van Golen
D017209:Apoptosis; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D058922:Inflammatory Breast Neoplasms / Q000201:enzymology* / Q000473:pathology*; D009361:Neoplasm Invasiveness; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction; D013379:Substrate Specificity; D020741:rho GTP-Binding Proteins / Q000378:metabolism*; D000075024:rhoC GTP-Binding Protein
D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C066690:RHOC protein, human; D020741:rho GTP-Binding Proteins; D000075024:rhoC GTP-Binding Protein