Downregulation of the circadian clock gene period 2 aggravates prognosis in breast cancer patients with obesityOACSTPCD

Background:Obese individuals diagnosed with breast cancer often experience a less favorable prognosis;however, the underlying mechanisms linking obesity to breast cancer outcomes remain elusive. This study aimed to identify and validate novel prognostic markers associated with breast cancer in patients with obesity. Methods:We conducted a reanalysis of gene expression profiles from normal-weight, overweight, and obese breast cancer patients to identify candidate genes. Subsequently, we validated the protein levels of these candidates using immunohistochemistry. Finally, we inves-tigated the association between candidate genes and breast cancer prognosis at Tongji Hospital, utilizing data from an 8-year follow-up through the Kaplan-Meier method and univariate and multivariate Cox regression models. Results:The fold change of the circadian clock gene period 2 (PER2), which exhibited a declining trend with increasing body mass index, was 0.76 in obese patients compared with normal-weight patients. The expression rates of PER2 protein were 44.7％, 51.5％, and 61.3％in normal-weight, overweight, and obese patients, respectively. The 8-year recurrence-free survival rates were 75.9％, 69.6％, and 64.1％, whereas the 8-year overall survival rates were 86.8％, 83.0％, and 76.1％in normal-weight, overweight, and obese patients, respectively ( P< 0.05). Furthermore, the 8-year recurrence-free survival rates were 66.2％ and 76.4％, and the 8-year overall survival rates were 79.9％and 86.3％in the low and high PER2 expression groups, respectively ( P<0.05). The un-adjusted hazard ratio for PER2 was 1.550 (95％confidence interval, 1.029–2.335), and the adjusted hazard ratio was 3.003 (95％confidence interval, 1.838–4.907). Conclusions:Our findings indicate that low PER2 expression serves as an independent risk factor for breast cancer prognosis and may contribute to the unfavorable outcomes observed in obese patients.