Preferential estrogen receptor β ligands reduce Bcl-2 expression in hormone-resistant breast cancer cells to increase autophagy.
Acquired resistance to selective estrogen receptor (ER) modulators (SERM) and downregulators (SERD) is a significant clinical problem in the treatment of estrogen (E2) receptor-positive (ER(+)) breast cancers. There are two ER subtypes, ERα and ERβ, which promote and inhibit breast cancer cell proliferation, respectively. Although ER(+) breast cancers typically express a high ratio of ERα to ERβ, the acquisition of SERM resistance in vitro and in vivo is associated with increased relative expression of the ERβ. On some gene enhancers, ERβ has been shown to function in opposition to the ERα in the presence of E2. Here, we demonstrate that two different ERβ agonists, WAY-20070 and a novel "A-CD" estrogen called L17, produce a marked reduction in G(2)-M phase correlated with effects on cyclin D1 and cyclin E expression in a SERM/SERD-resistant breast cancer cell line. ERβ agonists recruited both the ERα and ERβ to the Bcl-2 E2-response element strongly reducing Bcl-2 mRNA and protein in an ERβ-dependent manner. L17 recruited RIP140 to the Bcl-2 promoter in cells overexpressing ERβ. Exposure to the ERβ ligands also resulted in increased processing of LC3-I to LC3-II, indicative of enhanced autophagic flux. The coaddition of ERβ agonist and the autophagy inhibitor chloroquine resulted in a significant accumulation of sub-G1 DNA which was completely prevented by the addition of the caspase inhibitor Z-VAD-FMK. We propose that combined therapies with an ERβ agonist and an inhibitor of autophagy may provide the basis for a novel approach to the treatment of SERM/SERD-resistant breast cancers.
Authors' Affiliations: Departments of Cellular and Molecular Medicine and.
Samantha C
SC
Ruddy
Authors' Affiliations: Departments of Cellular and Molecular Medicine and.
Rosanna
R
Lau
Authors' Affiliations: Departments of Cellular and Molecular Medicine and.
Miguel A
MA
Cabrita
Authors' Affiliations: Departments of Cellular and Molecular Medicine and.
Chelsea
C
McGregor
Cancer Therapeutics Program, Ottawa Hospital Research Institute and the Departments of Medicine, and Cellular and Molecular Medicine, University of Ottawa;
Bruce C
BC
McKay
Manitoba Institute of Cell Biology, University of Manitoba, Winnipeg, Manitoba, Canada.
Leigh C
LC
Murphy
Department of Chemistry, Carleton University, Ottawa, Ontario; and.
James S
JS
Wright
Chemistry;
Tony
T
Durst
Authors' Affiliations: Departments of Cellular and Molecular Medicine and cpratt@uottawa.ca.
M A Christine
MA
Pratt
D001343:Autophagy / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008024:Ligands; D010080:Oxazoles / Q000494:pharmacology*; D010636:Phenols / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis*; D020845:Selective Estrogen Receptor Modulators / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects
D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; D010080:Oxazoles; D010636:Phenols; D019253:Proto-Oncogene Proteins c-bcl-2; D020845:Selective Estrogen Receptor Modulators; C502077:WAY 200070