Intermittent Hypoxia: Potential Factor of Resistance to Endocrine Therapy.

Abstract Background: It has been reported that intermittent hypoxia, which is likely more prevalent than acute hypoxia in breast cancers, can cause persistent depression of estrogen receptor alpha (ER-α) expression in breast cell lines. However, it remains suspension whether intermittent hypoxia may be associated with resistance to endocrine therapy.Material and methods: The role of intermittent hypoxia in resistance to endocrine therapy was investigated in ER-α positive breast cell lines and animal models.Results: We observed that intermittent hypoxia promoted cancer cell proliferation in vitro and in vivo compared with normoxia. At both mRNA and protein levels, intermittent hypoxia induced down-regulation of ER-α and factor inhibiting HIF-1 (FIH) as well as up-regulation of hypoxia inducible factor-1 alpha (HIF-1α) and carbonic anhydrase IX (CA-IX). ER-α positive breast cancer cells under normoxic condition were capable of an intact response to ICI 182,780 (Tocris), whereas the inhibitory effect of ICI 182,780 (Tocris) was significantly reduced in those after intermittent hypoxia. Such effect was further validated with fulvestrant (Astrazeneca) in the animal models. To clarify whether intermittent hypoxia was associated with resistance to endocrine therapy, the expression of HIF-1α, a critical regulator of hypoxia-related pathway, was blocked by a reformed type of small interfering RNA (siRNA), stealth RNAi (Invitrogen), which can reduce the cytotoxic interferon response unlike conventional siRNA. Interestingly, knock-down of HIF-1α did result in the restoration of not only the ER-α expression but also the response to endocrine therapy, which was reproducible with administration of Bortezomib, a proteasome inhibitor of HIF-1α.Discussion: These data provide functional evidence that intermittent hypoxia may confer resistance to endocrine therapy in breast cancers through the crosstalk between HIF-1α and ER-α signaling, which holds a promise to overcome endocrine resistance. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5148.