G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

Abstract

Hormonally regulated survival factors can have an important role in breast cancer. Here we elucidate G1P3, a survival protein induced by interferons (IFNs), as a target of estrogen signaling and a contributor to poor outcomes in estrogen receptor-positive (ER þ ) breast cancer. Compared with normal breast tissue, G1P3 was upregulated in the malignant epithelium (50 Â higher) and was induced by estrogen ex vivo. In accord with its overexpression in early stages of breast cancer (hyperplasia and ductal carcinoma in situ), in morphogenesis assays G1P3 enhanced the survival of MCF10A acinar luminal cells causing hyperplasia by suppressing detachmentinduced loss of mitochondrial potential and apoptosis (anoikis). In cells undergoing anoikis, G1P3 attenuated the induction of Bim protein, a proapoptotic member of the Bcl-2 family and reversed the downmodulation of Bcl-2 protein. Downregulation of G1P3 induced spontaneous apoptosis in BT-549 breast cancer cells and significantly reduced the growth of ER þ breast cancer cell MCF7 (Pp0.01), further suggesting its prosurvival activity. In agreement with its induction by estrogen, G1P3 antagonized tamoxifen, an inhibitor of ER in MCF7 cells. More importantly, elevated expression of G1P3 was significantly associated with decreased relapsefree and overall survival in ER þ breast cancer patients (Pp0.01). Our studies suggest that elevated expression of G1P3 may perturb canonical tumor-suppressing activity of IFNs partly by affecting the balance of pro-and antiapoptotic members of Bcl-2 family proteins, leading to breast cancer development and resistance to therapies.

Systematic identification of anti-interferon function on hepatitis C virus genome reveals p7 as an immune evasion protein

“…P-triflouromethoxyphenylhydrazone (FCCP) transports protons across mitochondrial inner membranes and induces the depolarization of mitochondria potential (49). Consistent with previous studies (46)(47)(48), our results also suggest that IFI6-16 stabilizes the mitochondrial membrane potential, as shown by residual TMRM fluorescence signal even in cells treated with a low FCCP dose for 10 min (Fig. 6).…”

“…However, little was known about its function or the mechanism in blocking viral infection. Recent studies suggest that IFI6-16 plays a critical role in stabilizing cancer cells by inhibiting mitochondrial-mediated apoptosis (46,47), and it also regulates apoptosis in Dengue virus (DENV)-infected cells (48). To examine whether p7 counteracts with IFI6-16 to regulate the mitochondrial function, we performed a mitochondrial membrane potential (Δψ) assay using a well-characterized potentiometric fluorescent dye, tetramethylrhodamine methyl ester (TMRM).…”

Thymoquinone regulates gene expression levels in the estrogen metabolic and interferon pathways in MCF7 breast cancer cells

“…The findings of our study revealed the downregulation of the IFI27 and IFI6 genes by 3.19- and 7.86-fold, respectively following treatment with thymoquinone. The downregulation of the IFI6 or GIP3 gene has been shown to reduce MCF-7 cell growth (33). …”

Molecular Pathways: Interferon/Stat1 Pathway: Role in the Tumor Resistance to Genotoxic Stress and Aggressive Growth

“…IFI6 (G1P3) suppresses replication of yellow fever virus YFV (59). IFI6 was also recently recognized as an antiapoptotic protein associated with tamoxifen-resistant aggressive breast cancers (60). USP18 (UBP43) is involved in the regulation of the stability of antiviral proteins, modified by ISG15.…”