Endocrine
therapy for
breast cancer often leads to drug resistance and
tumor recurrence; tumor hypoxia is also associated with mortality and
tumor relapse.
Cytochrome P450 1B1 (CYP1B1) regulates
estrogen metabolism in breast cells and is known to be overexpressed in
breast cancer tissue. Although the individual association of
hypoxia-induced
hypoxia-inducible factor-1-alpha (HIF-1α) and CYP1B1 with
tumorigenesis is well known, the association between HIF-1α and CYP1B1 leading to
tumorigenesis has not been investigated. Here, we investigated the correlation between
hypoxia and CYP1B1 expression in
breast cancer cells for
tumorigenesis-related mechanisms.
Hypoxia was induced in the human
breast cancer cell lines MCF-7 (Er-positive) and MDA-MB-231 (triple-negative) and the normal breast epithelial cell line MCF10A; these cell lines were then subjected to immunoblotting, transient transfection,
luciferase assays, gene silencing using
small interfering RNA, polymerase chain reaction analysis,
chromatin immunoprecipitation, co-immunoprecipitation, and mammalian two-hybrid assays. Furthermore, immunofluorescence analysis of the
tumor microarrays was performed, and the pub2015 and the
Cancer Genome Atlas patient datasets were analyzed. HIF-1α expression in response to
hypoxia occurred in both normal and
breast cancer cells, whereas CYP1B1 was induced only in
estrogen receptor α (ERα)-positive
breast cancer cells under
hypoxia. HIF-1α activated ERα through direct binding and in a
ligand-independent manner to promote CYP1B1 expression. Therefore, we suggested the mechanism by which
hypoxia and ER-positivity orchestrate
breast cancer relapse.