(6) mRNAs and protein expressions of elongation factors were also downregulated by BTG2<sup>/TIS21</sup> expression in TNBC cells, but much higher in both TIS21-KO mice and lymph node-positive human breast cancers.
Hypoxia up-regulated 1, BTG family member 2 and endothelin 1 may be associated with the progression of breast cancer through interaction with CtBP in different biological processes.
Consistent with this observation, tamoxifen significantly suppressed the growth ratio, tumor weight and Ki-67 expression in BTG2 expressing breast cancer xenografts in mice.
Several key regulators of early cell cycle progression such as Btg2 and cyclin D1, as well as regulators of mitosis, including cyclin B, Plk1, survivin, and aurora kinase A, were identified as novel targets for FGF-8b, some of which were additionally shown to correlate with prognosis and ER status in human breast cancer.
These results link BTG2-dependent effects on tumor progression to ErbB receptor signaling, and raise the possibility that targeted inhibition of this pathway may be relevant in the treatment of breast cancers that have reduced BTG2 expression.
Consistent with its ability to suppress cyclin D1 transcription, loss of nuclear BTG2 expression in ER-positive breast carcinomas showed a significant correlation with cyclin D1 protein overexpression, suggesting that loss of BTG2 may be a factor involved in deregulating cyclin D1 expression in human breast cancer.
To better understand the DeltaNp73-mediated transactivation of the BTG2TIS21/PC3 gene we performed luciferase assays with two reporter plasmids harboring long and short BTG2 promoter sequences in three human neuroblastoma cell lines and one breast cancer cell line.
BTG2 expression was very low or undetectable in human breast cancer cell lines compared with nontumorigenic mammary epithelial cells, and nuclear expression of BTG2 was absent in 65% of human breast tumors compared with adjacent matched normal glands.