Loss of G-Protein Pathway Suppressor 2 Promotes Tumor Growth Through Activation of AKT Signaling

Abstract

G Protein Suppressor 2 (GPS2) is a multifunctional protein that exerts important roles in inflammation and metabolism in adipose, liver, and immune cells. GPS2 has recently been identified as a significantly mutated gene in breast cancer and other malignancies and proposed to work as a putative tumor suppressor. However, molecular mechanisms by which GPS2 prevents cancer development and/or progression are largely unknown. Here, we have profiled the phenotypic changes induced by GPS2 depletion in MDA-MB-231 triple negative breast cancer cells and investigated the underlying molecular mechanisms. We found that GPS2-deleted MDA-MB-231 cells exhibited increased proliferative, migratory, and invasive properties in vitro, and conferred greater tumor burden in vivo in an orthotopic xenograft mouse model. Transcriptomic, proteomic and phospho-proteomic profiling of GPS2-deleted MBA-MB-231 revealed a network of altered signals that relate to cell growth and PI3K/AKT signaling. Overlay of GPS2-regulated gene expression with MDA-MB-231 cells modified to express constitutively active AKT showed significant overlap, suggesting that sustained AKT activation is associated with loss of GPS2. Accordingly, we demonstrate that the pro-oncogenic phenotypes associated with GPS2 deletion are rescued by pharmacological inhibition of AKT with MK2206. Collectively, these observations confirm a tumor suppressor role for GPS2 and reveal that loss of GPS2 promotes breast cancer cell proliferation and tumor growth through uncontrolled activation of AKT signaling. Moreover, our study points to GPS2 as a potential biomarker for a subclass of breast cancers that would be responsive to PI3K-class inhibitor drugs.

A Novel Risk Model Based on Lipid Metabolism-Associated Genes Predicts Prognosis and Indicates Immune Microenvironment in Breast Cancer

“…Finally, GPS2 encodes G protein suppressor 2 (GPS2), which was identified as a constituent of the silencing mediator of retinoic acid and thyroid hormone receptor corepressor complexes ( Cheng and Kao, 2009 ). GPS2 has been shown to play a tumor-suppressive role in liposarcoma ( Huang et al, 2016 ) and BRCA ( Cheng and Kao, 2009 ; Chan et al, 2020 ), and the loss of GPS2 facilitated tumor growth and the proliferation of cancer cells ( Chan et al, 2020 ). These findings indicate that the aberrant expression of the candidate LMAGs is involved in the progression and prognosis of multiple types of tumors, including BRCA; therefore, it was reasonable to integrate them to establish a risk model for risk stratification and prognosis prediction in BRCA.…”

Targeting Akt in cancer for precision therapy

“… [ 254 , 255 ] NPM1 mutation AML [ 257 ] NM23-H1 Breast cancer, melanoma, etc. [ 248 ] CBL mutation Myeloid neoplasmas [ 249 ] BTK mutation or deficiency Follicular lymphoma [ 253 ] GPS2 mutation Breast cancer, medulloblastoma [ 250 – 252 ] CDH1 mutation or deficiency Gastric cancer, breast cancer, prostate cancer, colorectal cancer, ovarian cancer, etc. [ 261 , 262 ] SMAD4 mutation Colorectal cancer, pancreatic cancer [ 269 , 270 ] GAB2 mutation or amplification Hematological malignancies, ovarian cancer, lung cancer, neuroblastoma, melanoma, breast cancer [ 264 – 268 ] …”

“…It warrants further study to determine if CBL mutation can predict the sensitivity to Akt inhibitors. In addition, G protein pathway suppressor 2 (GPS2) is a significantly mutated gene in breast cancer, medulloblastoma and other tumors [ 250 – 252 ]. GPS2 depletion in breast cancer cells results in sustained PI3K/Akt signaling and increased cell proliferation, migration and invasion, which can be inhibited by MK2206 [ 250 ].…”

“…In addition, G protein pathway suppressor 2 (GPS2) is a significantly mutated gene in breast cancer, medulloblastoma and other tumors [ 250 – 252 ]. GPS2 depletion in breast cancer cells results in sustained PI3K/Akt signaling and increased cell proliferation, migration and invasion, which can be inhibited by MK2206 [ 250 ]. Thus, GPS2 mutation may be a potential biomarker for the responsiveness to Akt inhibitors [ 250 ].…”

“…GPS2 depletion in breast cancer cells results in sustained PI3K/Akt signaling and increased cell proliferation, migration and invasion, which can be inhibited by MK2206 [ 250 ]. Thus, GPS2 mutation may be a potential biomarker for the responsiveness to Akt inhibitors [ 250 ].…”