Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer

Abstract

Background: Protacs (Proteolysis Targeting Chimeric molecules) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We hypothesized that these Protacs would recruit hormone receptors to the VHL E3 ligase complex, resulting in the degradation of receptors, and decreased proliferation of hormone-dependent cell lines. Materials and Methods: We designed two Protacs that contain the peptide 'degron' from HIF-1a, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone (DHT) that targets the androgen receptor (AR) (Protac-A), or linked to estradiol (E2) that targets the estrogen receptor a (ERalpha) (Protac-B). Both breast and prostate cancer cells were treated with Protacs. Inhibition of growth and the levels of ER and AR were determined. Results: Treatment of estrogen-dependent breast cancer cells, MCF-7 and T47D, with Protac-B induced the degradation of ERalpha in a proteasome-dependent manner. Protac-B inhibited the proliferation of ERalpha-dependent breast cancer cells by inducing G1 arrest, inhibition of retinoblastoma phosphorylation and decreasing expression of Cyclin D1, progesterone receptors A and B. Protac-B treatment did not affect the proliferation of estrogen-independent breast cancer cells that lacked ERalpha expression. Similarly, Protac-A treatment of androgen-dependent prostate cancer cells (LNCaP) induced G1 arrest but did not affect cells that do not express AR. Conclusions: Our results suggest that Protacs specifically inhibit the proliferation of hormone-dependent breast and prostate cancer cells through degradation of the ERalpha and AR respectively.

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