Estrogen receptor β represses Akt signaling in breast cancer cells via downregulation of HER2/HER3 and upregulation of PTEN: implications for tamoxifen sensitivity

Abstract

IntroductionThe inhibition of estrogen receptor (ER) α action with the ER antagonist tamoxifen is an established treatment in the majority of breast cancers. De novo or acquired resistance to this therapy is common. Expression of ERβ in breast tumors has been implicated as an indicator of tamoxifen sensitivity. The mechanisms behind this observation remain largely uncharacterized. In the present study, we investigated whether ERβ can modulate pathways implicated in endocrine resistance development.MethodsT47-D and MCF-7 ERα-expressing breast cancer cells with tetracycline-regulated expression of ERβ were used as a model system. Expression levels and activity of known regulators of endocrine resistance were analyzed by performing quantitative polymerase chain reaction assays, Western blot analysis and immunostaining, and sensitivity to tamoxifen was investigated by using a cell proliferation kit.ResultsExpression of ERβ in ERα-positive T47-D and MCF-7 human breast cancer cells resulted in a decrease in Akt signaling. The active form of an upstream regulator of Akt, proto-oncogene c-ErbB-2/receptor tyrosine kinase erbB-3 (HER2/HER3) receptor dimer, was also downregulated by ERβ. Furthermore, ERβ increased expression of the important inhibitor of Akt, phosphatase and tensin homologue deleted on chromosome 10 (PTEN). Importantly, ERβ expression increased the sensitivity of these breast cancer cells to tamoxifen.ConclusionsOur results suggest a link between expression of ERβ and endocrine sensitivity by increasing PTEN levels and decreasing HER2/HER3 signaling, thereby reducing Akt signaling with subsequent effects on proliferation, survival and tamoxifen sensitivity of breast cancer cells. This study supports initiatives to further investigate whether ERβ presence in breast cancer samples is an indicator for endocrine response. Current therapies in ERα-positive breast cancers aim to impair ERα activity with antagonists or by removal of endogenous estrogens with aromatase inhibitors. Data from this study could be taken as indicative for also using ERβ as a target in selected groups of breast cancer.

Identification of Estrogen Receptor β as a SUMO-1 Target Reveals a Novel Phosphorylated Sumoylation Motif and Regulation by Glycogen Synthase Kinase 3β

“…GSK3␤ is active in resting cells through constitutive Tyr-216 phosphorylation, and PI3K/Akt-activating stimuli such as insulin can cause phosphorylation at Ser-9 and inactivation of GSK3␤ (8). The mechanism by which nongenomic activation of ER␤ might contribute to Ser-9 dephosphorylation and GSK3␤ activation in our study is still uncertain, but recent findings in rodent brain capillaries and breast cancer cells have shown that sustained ER␤ activation by extended exposure to estradiol resulted in PTEN activation and decreased GSK3 phosphorylation (19,27). Interestingly, part of the mechanism involved might also refer to the ER␤ response to Akt activation, as we demonstrated that activation of the PI3K/Akt pathway downregulated ER␤ degradation and activity in breast cancer cells (38).…”

Estrogen receptor beta (ERβ) produces autophagy and necroptosis in human seminoma cell line through the binding of the Sp1 on the phosphatase and tensin homolog deleted from chromosome 10 (PTEN) promoter gene

“…35 We demonstrated that this effect occurs through a genomic action by performing transient transfection experiments with plasmid constructs containing progressively deleted regions in the 5'-flanking region of the PTEN promoter. Interestingly, the segment located between -1398 and -1118 from the transcription start 59 kDa, whereas two different Abs used in the evaluation of ERα expression did not show a 67 kDa signal, as reported for the classical ERα.…”

Role of estrogen receptor β in gynecological cancer

“…Thus, the reason for the relative high endocrine resistance of ovarian cancer remains to be solved. In breast cancer, recent results suggested ERβ to be a predictive marker for good response to antiestrogens, although some contradictory data exist [6,[41][42][43][44][45][46]. In a recent study, we showed that long-time treatment with tamoxifen in vitro triggered endocrine resistance in ovarian cancer cells, an effect which was accompanied by ERβ downregulation, whereas expression of ERα or HER family kinases was not altered [17].…”