Abstract
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.
Highlights
The estrogen receptors (ER) are ligand-dependent nuclear receptors that contain a DNA-binding domain, ligand-binding domain, an N-terminal transcriptional activating function AF-1, and a C-terminal AF-2 [1]
The expression of ERa is similar in both MCF-7 lines the level of ERb is reduced in MCF7CL cells relative to MCF-7PL cells demonstrating significant variation across isolates of MCF-7 cells
ERa was reduced in LCC1 cells, whereas the ERb was increased relative to parental MCF-7CL cells
Summary
The estrogen receptors (ER) are ligand-dependent nuclear receptors that contain a DNA-binding domain, ligand-binding domain, an N-terminal transcriptional activating function AF-1, and a C-terminal AF-2 [1]. There are two subtypes called ERa and ERb which can either form homodimers or heterodimers to transactivate responsive genes in the presence of E2. The ERa has a strong ligand independent AF-1 region, the ERb AF-1 function is weaker [2] and mediates a dominant negative effect on ERa as a result of an N-. Several groups have demonstrated that ectopic expression of the ERb in ERaþ breast cancer cells results in growth inhibition [6, 7] and prevents xenograft formation in nude mice in response to E2 [7]. ERb regulates gene transcription in an E2-independent and dependent manner with downstream effects impacting on cell-cycle progression [8, 9]. Cyclin D1 is positively regulated by the ERa and negatively regulated by the ERb in the presence of E2 [7]
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