α9-nAChR 是烟碱乙酰胆碱受体的一种亚型，与正常组织相比，在女性乳腺癌肿瘤组织中显着过度表达。先前的研究提出，CHRNA9 (α9-nAChR) 基因中的特定单核苷酸多态性 (SNP) 与吸烟导致的乳腺癌风险增加有关。该研究对台湾女性人群（包括 308 名乳腺癌患者和 198 名健康对照）中的 α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A > G) 进行乳腺癌风险评估，结果显示，携带 A/G 杂合子的个体与 G/G 变异基因型携带者相比，A/A 野生基因型在吸烟的情况下患乳腺癌的易感性增加。我们的研究证实了这种错义变异的存在，导致氨基酸序列从天冬酰胺 (N442) 改变为丝氨酸 (S442)，以促进 α9-nAchR 蛋白内的磷酸化。此外，与 S442 (G/G) 相比，乳腺癌细胞中 N442 (A/A) 的过表达显着增强了细胞存活、迁移和癌症干性。具有独特 α9-nAChR rs10009228 SNP 基因型（A/A、A/G、G/G）的四系三阴性乳腺癌患者来源的异种移植（TNBC-PDX）模型进一步证明，长期尼古丁暴露通过持续的尼古丁加速肿瘤生长α9-nAChR 下游致癌 AKT/ERK/STAT3 通路的激活，特别是在具有 A/G 或 A/A 基因型的个体中。总的来说，我们的研究确定了 α9-nAChR 的遗传变异与吸烟促进乳腺肿瘤发展之间的联系。这强调在制定有效的乳腺癌预防和治疗策略时需要仔细考虑基因与环境的相互作用。© 作者 2024。由牛津大学出版社出版。版权所有。如需权限，请发送电子邮件至：journals.permissions@oup.com。

α9-nAChR, a subtype of nicotinic acetylcholine receptor, is significantly overexpressed in female breast cancer tumor tissues compared to normal tissues. Previous studies have proposed that specific single nucleotide polymorphisms (SNPs) in the CHRNA9 (α9-nAChR) gene are associated with an increased risk of breast cancer in interaction with smoking. The study conducted a breast cancer risk assessment of the α9-nAChR SNP rs10009228 (NM_017581.4:c.1325A > G) in the Taiwanese female population, including 308 breast cancer patients and 198 healthy controls revealed that individuals with the heterozygous A/G or A/A wild genotype have an increased susceptibility to developing breast cancer in the presence of smoking compared to carriers of the G/G variant genotype. Our investigation confirmed the presence of this missense variation, resulting in an alteration of the amino acid sequence from asparagine (N442) to serine (S442) to facilitate phosphorylation within the α9-nAchR protein. Additionally, overexpression of N442 (A/A) in breast cancer cells significantly enhanced cell survival, migration, and cancer stemness compared to S442 (G/G). Four-line triple-negative breast cancer patient-derived xenograft (TNBC-PDX) models with distinct α9-nAChR rs10009228 SNP genotypes (A/A, A/G, G/G) further demonstrated that chronic nicotine exposure accelerated tumor growth through sustained activation of the α9-nAChR downstream oncogenic AKT/ERK/STAT3 pathway, particularly in individuals with the A/G or A/A genotype. Collectively, our study established the links between genetic variations in α9-nAChR and smoking exposure in promoting breast tumor development. This emphasizes the need to consider gene-environment interactions carefully while developing effective breast cancer prevention and treatment strategies.© The Author(s) 2024. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.