Low expression of Beclin 1 and elevated expression of HIF-1α refine distant metastasis risk and predict poor prognosis of ER-positive, HER2-negative breast cancer

Abstract

Even though ER-positive, HER2-negative breast tumors represent a subset of breast cancers with a better clinical outcome, approximately 12.7 % of patients in this subgroup ultimately develop cancer-related mortality. Recent studies had confirmed that hypoxia-induced autophagy-related gene Beclin 1 expression might be important for disease progression and be correlated with patient outcome in several tumors. Here, we examined the autophagic Beclin 1 and hypoxic HIF-1α levels in 378 ER-positive, HER2-negative breast cancer patients by immunohistochemistry using tissue microarray. We found that Beclin 1 was highly expressed in normal mammary gland epithelia. In contrast, it was either not expressed or only moderately expressed in 78.0 % of breast adenocarcinoma tissue. Compared to the subset overexpressing Beclin 1, the subset in which Beclin 1 levels were reduced had a poor 5-year overall survival rate (OS, 85.1 % vs. 94.1 %, P = 0.005) and a poor distant metastasis-free survival (DMFS, 79.1 % vs. 89.3 %, P = 0.037). Cox multivariate analysis confirmed that Beclin 1 was indeed an independent prognostic factor for OS and DMFS. Additionally, Beclin 1 positively correlated with HIF-1α expression (r = 0.206, P < 0.001). Importantly, among patients with HIF-1α overexpression, low levels of Beclin 1 predicted a worse OS. Our study confirmed that deficiency of Beclin 1 was a negative prognostic factor for OS and DMFS in ER-positive, HER2-negative breast cancer. The combination of Beclin 1 and HIF-1α refined the risk definition of the patient subset and provided a novel way to identify those with a high risk of relapse.