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Selective estrogen receptor (ER) modulators differentially regulate phospholipase D catalytic activity in ER-negative
Susanne F Eisen1, H Alex Brown
1Department of Molecular Medicine, Veterinary Medical Center, Field of Pharmacology, Cornell University, Ithaca, New York, USA.
Abstract:
Recent successes in the pharmacotherapeutic treatment of breast cancer are associated with the use of selective estrogen receptor modulators. Two commonly prescribed pharmaceuticals in this class, tamoxifen and raloxifene, have been shown to have effects through estrogen receptor (ER)-independent mechanisms. Hyperactivation of phospholipase D (PLD) in certain tumor-derived cell lines have been reported, and recent findings suggest a role for PLD in transformation and metastasis. In the present study, we compare the effects of tamoxifen and raloxifene on PLD in the ER-positive mammary epithelial cell line MCF-12A, and the ER-negative, highly tumorigenic mammary carcinoma cell line MDA-MB-231. Our data demonstrate that tamoxifen and raloxifene have differential effects on PLD catalytic activity. Tamoxifen stimulates PLD in both ER-positive and -negative cells in vivo, whereas raloxifene inhibits PLD activity in these same cell types. In addition, we show that the active metabolite 4-OH-tamoxifen can be used to pharmacologically discriminate the two isoforms of PLD, through a stimulatory effect on PLD1 and an inhibitory effect on PLD2. Using recombinant PLD1, we show stimulation by tamoxifen requires a factor present in Sf21 insect cells that is not required for inhibition of PLD1 by raloxifene. Furthermore, tamoxifen stimulation and raloxifene inhibition of PLD activities are independent of the amino-terminal portion of PLD1 (amino acids 1-324). Knowledge of the mechanisms of action of these drugs on PLD may provide insights into the pharmacological action of these drugs and the role of PLD in some cancers.
Insights
Tamoxifen and raloxifene show distinct effects on phospholipase D (PLD) activity in breast cancer cells. Tamoxifen stimulates PLD, while raloxifene inhibits it, offering potential new therapeutic strategies.
Area of Science:
- Biochemistry
- Pharmacology
- Cancer Biology
Background:
- Selective estrogen receptor modulators (SERMs) like tamoxifen and raloxifene are key in breast cancer pharmacotherapy.
- ER-independent mechanisms and the role of phospholipase D (PLD) in cancer progression are emerging areas of research.
Purpose of the Study:
- To investigate the differential effects of tamoxifen and raloxifene on PLD activity in both ER-positive and ER-negative breast cancer cell lines.
- To explore the potential of PLD modulation as a therapeutic target in breast cancer.
Main Methods:
- Comparative analysis of tamoxifen and raloxifene's impact on PLD catalytic activity in MCF-12A (ER-positive) and MDA-MB-231 (ER-negative) cell lines.
- Investigation of the effects of 4-OH-tamoxifen on PLD1 and PLD2 isoforms.
- Studies using recombinant PLD1 to elucidate mechanisms of tamoxifen and raloxifene action.
Main Results:
- Tamoxifen stimulates PLD activity in both ER-positive and -negative cells.
- Raloxifene inhibits PLD activity in both cell types.
- 4-OH-tamoxifen differentially affects PLD1 (stimulatory) and PLD2 (inhibitory), allowing pharmacological discrimination.
Conclusions:
- Tamoxifen and raloxifene exhibit opposing effects on PLD activity, suggesting distinct mechanisms of action.
- The differential modulation of PLD isoforms by tamoxifen metabolites provides insights into SERM pharmacology.
- Understanding these PLD-related mechanisms may enhance breast cancer treatment strategies.