Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer

You-Cheng Liao; Lu-Hai Wang; Mien-Chie Hung; Tzu-Chun Cheng; Ying-Chi Lin; Jungshan Chang; Shih-Hsin Tu; Chih-Hsiung Wu; Yun Yen; Yi-Chen Hsieh; Li-Ching Chen; Yuan-Soon Ho

doi:10.1093/hmg/ddae132

Investigation of the α9-nicotinic receptor single nucleotide polymorphisms induced oncogenic properties and molecular mechanisms in breast cancer

Hum Mol Genet. 2024 Sep 10:ddae132. doi: 10.1093/hmg/ddae132. Online ahead of print.

Authors

You-Cheng Liao¹, Lu-Hai Wang^{2

3}, Mien-Chie Hung^{4

5}, Tzu-Chun Cheng⁶, Ying-Chi Lin⁷, Jungshan Chang^{1

8}, Shih-Hsin Tu⁹, Chih-Hsiung Wu⁹, Yun Yen¹⁰, Yi-Chen Hsieh¹¹, Li-Ching Chen⁷, Yuan-Soon Ho⁶

Affiliations

¹ Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
² Chinese Medicine Research Center, China Medical University, Taichung 404328, Taiwan.
³ Graduate Institute of Integrated Medicine, China Medical University, Taichung 404328, Taiwan.
⁴ Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 406040, Taiwan.
⁵ Department of Biotechnology, Asia University, Taichung 413305, Taiwan.
⁶ Institute of Biochemistry and Molecular Biology, College of Life Sciences, China Medical University, Taichung 406040, Taiwan.
⁷ Department of Biological Science & Technology, College of Life Sciences, China Medical University, Taichung 406040, Taiwan.
⁸ International Master/Ph.D. Program in Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
⁹ Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 110301, Taiwan.
¹⁰ TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 110301, Taiwan.
¹¹ PhD Program in Medical Neuroscience, College of Medical Science and Technology, Taipei Medical University, Taipei 110301, Taiwan.

PMID: 39251229
DOI: 10.1093/hmg/ddae132

Abstract

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.

Keywords: Breast cancer; Patient derived xenograft (PDX); Single-nucleotide polymorphisms (SNPs); Smoking exposure; α9-nicotinic acetylcholine receptor (α9-nAChR).

Abstract

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