Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Query: EC:2.6.1.19 (
GABA transaminase
)
808
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Basal-like breast cancer (BLBC) is the most aggressive subtype with a poor clinical outcome; however, the molecular mechanisms underlying
aggressiveness
in BLBC remain poorly understood.
Methods:
The effects of gamma-aminobutyrate aminotransferase (
ABAT
) on GABA receptors, Ca
2+
-NFAT1 axis, and cancer cell behavior were assessed by Ca
2+
imaging, Western blotting, immunostaining, colony formation, and migration and invasion assays. We elucidated the relationship between
ABAT
and Snail by luciferase reporter and ChIP assays. The effect of
ABAT
expression on BLBC cells was determined by
in vitro
and
in vivo
tumorigenesis and a lung metastasis mouse model.
Results:
We showed that, compared to other subtypes,
ABAT
was considerably decreased in BLBC. Mechanistically,
ABAT
expression was downregulated due to Snail-mediated repression leading to increased GABA production. GABA then elevated intracellular Ca
2+
concentration by activating GABA-A receptor (GABA
A
), which contributed to the efficient activation of NFAT1 in BLBC cells.
ABAT
expression resulted in inhibition of tumorigenicity, both
in vitro
and
in vivo
, and metastasis of BLBC cells. Thus, loss of
ABAT
contributed to BLBC
aggressiveness
by activating the Ca
2+
-NFAT1 axis. In breast cancer patients, loss of
ABAT
expression was strongly correlated with large tumor size, high grade and metastatic tendency, poor survival, and chemotherapy resistance.
Conclusions:
Our findings have provided underlying molecular details for the aggressive behavior of BLBC. The Snail-mediated downregulation of
ABAT
expression in BLBC provides tumorigenic and metastatic advantages by activating GABA-mediated Ca
2+
-NFAT1 axis. Thus, our results have identified potential prognostic indicators and therapeutic targets for this challenging disease.
...
PMID:Loss of ABAT-Mediated GABAergic System Promotes Basal-Like Breast Cancer Progression by Activating Ca
2+
-NFAT1 Axis. 3066 52
