title: Targeting steroid hormone receptors for ubiquitination and degradation in breast and prostate cancer.
abstract: Proteolysis targeting chimeric molecules (Protacs) target proteins for destruction by exploiting the ubiquitin-dependent proteolytic system of eukaryotic cells. We designed two Protacs that contain the peptide 'degron' from hypoxia-inducible factor-1alpha, which binds to the Von-Hippel-Lindau (VHL) E3 ubiquitin ligase complex, linked to either dihydroxytestosterone that targets the androgen receptor (AR; Protac-A), or linked to estradiol (E2) that targets the estrogen receptor-alpha (ERalpha; Protac-B). 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. Treatment of estrogen-dependent breast cancer cells 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 G(1) 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 induced G(1) arrest but did not affect cells that do not express AR. 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.
authors.affiliation: Department of Pediatrics, Gwynne Hazen Cherry Laboratories, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095-1752, USA.
authors.forename: A
authors.initials: A
authors.lastname: Rodriguez-Gonzalez
authors.forename: K
authors.initials: K
authors.lastname: Cyrus
authors.forename: M
authors.initials: M
authors.lastname: Salcius
authors.forename: K
authors.initials: K
authors.lastname: Kim
authors.forename: C M
authors.initials: CM
authors.lastname: Crews
authors.forename: R J
authors.initials: RJ
authors.lastname: Deshaies
authors.forename: K M
authors.initials: KM
authors.lastname: Sakamoto
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000737:chemistry; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D013196:Dihydrotestosterone / Q000008:administration & dosage / Q000378:metabolism; D016503:Drug Delivery Systems / Q000379:methods*; D004958:Estradiol / Q000008:administration & dosage / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000187:drug effects / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000008:administration & dosage / Q000737:chemistry; D008297:Male; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects; D011944:Receptors, Androgen / Q000187:drug effects / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000737:chemistry; D054875:Ubiquitination / Q000502:physiology*
chemical_list: D000970:Antineoplastic Agents; D047628:Estrogen Receptor alpha; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D011944:Receptors, Androgen; D011987:Receptors, Steroid; D011993:Recombinant Fusion Proteins; D013196:Dihydrotestosterone; D004958:Estradiol; D046988:Proteasome Endopeptidase Complex
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