The Dual Estrogen Receptor α Inhibitory Effects of the Tissue-Selective Estrogen Complex for Endometrial and Breast Safety.
The conjugated estrogen /: bazedoxifene tissue-selective estrogen complex (TSEC) is designed to minimize the undesirable effects of estrogen in the uterus and breast tissues and to allow the beneficial effects of estrogen in other estrogen-target tissues, such as the bone and brain. However, the molecular mechanism underlying endometrial and breast safety during TSEC use is not fully understood. Estrogen receptor α (ERα)-estrogen response element (ERE)-DNA pull-down assays using HeLa nuclear extracts followed by mass spectrometry-immunoblotting analyses revealed that, upon TSEC treatment, ERα interacted with transcriptional repressors rather than coactivators. Therefore, the TSEC-mediated recruitment of transcriptional repressors suppresses ERα-mediated transcription in the breast and uterus. In addition, TSEC treatment also degraded ERα protein in uterine tissue and breast cancer cells, but not in bone cells. Interestingly, ERα-ERE-DNA pull-down assays also revealed that, upon TSEC treatment, ERα interacted with the F-box protein 45 (FBXO45) E3 ubiquitin ligase. The loss-of- and gain-of-FBXO45 function analyses indicated that FBXO45 is involved in TSEC-mediated degradation of the ERα protein in endometrial and breast cells. In preclinical studies, these synergistic effects of TSEC on ERα inhibition also suppressed the estrogen-dependent progression of endometriosis. Therefore, the endometrial and breast safety effects of TSEC are associated with synergy between the selective recruitment of transcriptional repressors to ERα and FBXO45-mediated degradation of the ERα protein.
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Sang Jun
SJ
Han
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Khurshida
K
Begum
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Charles E
CE
Foulds
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Ross A
RA
Hamilton
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Suzanna
S
Bailey
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Anna
A
Malovannaya
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Doug
D
Chan
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas.
Jun
J
Qin
Department of Molecular and Cellular Biology (S.J.H., K.B., C.E.F., R.A.H, S.B., A.M., D.C., J.Q., B.W.O.), And Center for Molecular Discovery, Verna and Marrs McLean, Department of Biochemistry and Molecular Biology (A.M., D.C., J.Q.), Baylor College of Medicine, Houston, Texas berto@bcm.edu.
Bert W
BW
O'Malley
D000818:Animals; D001940:Breast / Q000187:drug effects / Q000378:metabolism; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D004715:Endometriosis / Q000188:drug therapy* / Q000378:metabolism; D004717:Endometrium / Q000187:drug effects / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology / Q000627:therapeutic use; D004966:Estrogens, Conjugated (USP) / Q000494:pharmacology* / Q000627:therapeutic use*; D005260:Female; D006367:HeLa Cells; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008810:Mice, Inbred C57BL; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology / Q000627:therapeutic use
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D004967:Estrogens; D004966:Estrogens, Conjugated (USP); D020845:Selective Estrogen Receptor Modulators