BNIP3 expression in endometrial cancer relates to active hypoxia inducible factor 1á pathway and prognosis

Abstract

Aims: BNIP3 is a pro-apoptotic mitochondrial protein induced under hypoxic stress with the BNIP3 gene being under direct regulation of the hypoxia inducible HIF1á transcription factor. Induction of BNIP3 leads to caspase-independent necrosis-like cell death and an aggressive tumor phenotype. We examined the role of BNIP3 in endometiral cancer.

Methods: The immunohistochemical patterns of BNIP3 expression in 72 early endometrial adenocarcinomas of the endometrioid cell type were studied. Correlation of BNIP3 with the hypoxia inducible factor HIF1á-pathway and with prognosis was also examined.

Results: BNIP3 was strongly and extensively expressed in the cytoplasm of cancer cells in 23/72 (31.9%) cases. This high BNIP3 reactivity was not related to histological grade, the depth of myometrial invasion or steroid hormone receptor expression. There was, however, a significant association of BNIP3 reactivity with HIF1á (p=0.05), VEGF (p=0.05) and, particularly, LDH-5 expression (p<0.0001). Furthermore, high BNIP3 was associated with poor survival in both univariate and multivariate models.

Conclusion: BNIP3 seems to be an important hypoxia-regulated molecule involved in endometrial cancer pathology. Given that high BNIP3 reactivity, being linked with poor post-operative outcome, has been linked with a favourable response to cytotoxic therapy (as previously indicated in experimental studies), high BNIP3 expression may be an indicator for adjuvant chemo-radiotherapy in stage I endometrial carcinomas.