ATPase copper transporting beta attenuates malignant features with high expression as an indicator of favorable prognosis in breast cancer.

Background

ATPase copper transporting beta (ATP7B) functions as a copper-transporting ATPase that ejects copper from cells. Although high expression of ATP7B has been reported to increase cisplatin resistance, its role in breast cancer (BC) remains unclear. This study aimed to elucidate the function of ATP7B in BC cells and its significance in patients with BC.

Methods

The mRNA and protein expression levels of ATP7B were evaluated in BC and non-cancerous mammary cell lines. Polymerase chain reaction (PCR) array analysis was conducted to determine the correlation between ATP7B and 84 cancer-related genes. ATP7B knockdown was performed using small interfering RNA, and cell proliferation, invasiveness, and migration were analyzed. The associations between the mRNA and protein expression of ATP7B and clinicopathological factors were also investigated in 156 patients with BC.

Results

ATP7B was found to be highly expressed in estrogen receptor-positive and human epidermal growth factor receptor 2-positive BC cell lines. PCR array analysis revealed a significant correlation between the expression level of ATP7B and those of cadherin 1, estrogen receptor 1, and MET proto-oncogene. ATP7B knockdown significantly increased the proliferation, invasiveness, and migration of MDA-MB-361 and MDA-MB-415 cells. Patients with high ATP7B expression at the mRNA and protein levels experienced favorable prognoses. In addition, ATP7B expression level was identified as an independent prognostic factor in multivariate analysis.

Conclusions

ATP7B is involved in promoting anti-cancer activities of tumor suppressors in BC cells across different subtypes and is considered a prognostic marker for BC.

COI Statement

Declarations. Conflict of interest: Norikazu Masuda received a research grant from Chugai Pharma, Eli Lilly Japan, AstraZeneca, Pfizer, Daiichi Sankyo, MSD, Eisai, Novartis, Gilead Sciences, and Ono Pharma; received lecture fees from Chugai Pharma, Pfizer, AstraZeneca, Eli Lilly Japan, Daiichi Sankyo, and Eisai; and is a board representative of the Japan Breast Cancer Research Group (JBCRG) and a board member of the Japanese Breast Cancer Society (JBCS), the Japan Society of Clinical Oncology (JSCO), and the Japan Association of Breast Cancer Screening (JABCS), all without remuneration. The other authors declare no competing interests. Ethics approval and consent to participate: The present study was approved by the Institutional Review Board and Ethics Committee of Nagoya University Hospital (approval no. 2019‑0028). Informed consent was obtained from all patients included in the study. Patient consent for publication: The participants provided written informed consent for publication as required by the Institutional Review Board and Ethics Committee of Nagoya University Hospital.

References:

• Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin. 2023;73:17–48.
• Palmgren MG, Nissen P. P-type ATPases. Annu Rev Biophys. 2011;40:243–66.
• Polishchuk EV, Merolla A, Lichtmannegger J, Romano A, Indrieri A, Ilyechova EY, et al. Activation of autophagy, observed in liver tissues from patients with wilson disease and from ATP7B-deficient animals, protects hepatocytes from copper-induced apoptosis. Gastroenterology. 2019;156(1173–89): e5.
• Li YQ, Yin JY, Liu ZQ, Li XP. Copper efflux transporters ATP7A and ATP7B: Novel biomarkers for platinum drug resistance and targets for therapy. IUBMB Life. 2018;70:183–91.
• Inesi G, Pilankatta R, Tadini-Buoninsegni F. Biochemical characterization of P-type copper ATPases. Biochem J. 2014;463:167–76.