ABAT在基底型乳腺癌的作用与机制研究

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. Here, we found that in contrast to other subtypes, gamma-aminobutyrate aminotransferase (ABAT) was dramatically downregulated in BLBC. We also noticed ABAT expression was remarkably downregulated by Snail, a transcriptional repressor of E-cadherin. Based on these findings, we propose that ABAT may associate with breast cancer cell proliferation and metastasis by regulating metabolic reprogramming. The objective of this proposal is to explore the potential roles of ABAT in tumorigenicity and metastasis of breast cancer cells. This study will uncover the important role of ABAT loss induced by Snail in regulating metabolic reprogramming in BLBC cells. Elucidating the correlation between ABAT and Snail will contribute to our understanding of how metabolic reprogramming regulating tumorigenicity and metastasis in BLBC, providing potential prognostic indicators and therapeutic targets for BLBC.

基底样亚型乳腺癌增殖活力高、抗药性强、复发率高、侵袭力和转移能力强、预后差，是恶性程度最高的乳腺癌亚型。目前，基底样乳腺癌的代谢调控机制尚不清楚。γ-氨基丁酸转氨酶(Gamma-aminobutyrate aminotransferase，ABAT）是γ-氨基丁酸(GABA)代谢过程中的一个关键酶。我们前期研究发现基底样乳腺癌细胞和组织标本的ABAT表达水平明显低于其它的亚型。此外，我们也发现Snail能够显著抑制ABAT的表达。在本申请项目中，我们将重点研究ABAT介导的代谢改变对基底样乳腺癌发生及转移的作用与分子机制，明确Snail对ABAT表达的调控机制，从体外和体内研究Snail/ABAT与基底样乳腺癌的内在联系。本项目的开展将不仅有助于理解ABAT介导的代谢改变对基底样乳腺癌的发生与转移的影响，也有助于为早期预防和治疗该型乳腺癌提供理论依据和潜在的标记分子。

乳腺癌是女性常见的癌症，而基底样型乳腺癌是恶性程度最高的乳腺癌亚型。深入研究基底样乳腺癌的分子调控机制有助于为预防和治疗该型乳腺癌提供理论依据和潜在的分子靶标。γ-氨基丁酸（GABA）属于一种非蛋白质氨基酸，是神经系统中重要的抑制性神经递质。ABAT能分解代谢GABA产生琥珀酸半醛。董辰方研究团队通过对5000余例乳腺癌患者的生物信息数据分析发现ABAT在基底样型腺癌中的表达显著降低，其低表达患者预后较差。进一步研究发现转录因子Snail能显著抑制ABAT的表达，从而增加GABA的产生。GABA通过激活GABA-A受体提高细胞内Ca2 +浓度，使细胞中NFAT1激活，从而增强基底样乳腺癌细胞在体外和体内的致瘤性和转移能力。本研究揭示了基底样型乳腺癌高侵袭力的分子调控机制，提示ABAT介导的GABA能系统的相关分子有潜力成为基底样乳腺癌的预测标志分子和治疗靶点。