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Additive interactions between bisphosphonates and ER antagonists in estrogen receptor-positive breast cancer cell lines
Bisphosphonates are standard therapy for the management of bone metastases from breast cancer. They are potent inhibitors of osteoclast-mediated tumor-stimulated osteolysis, and recent in vitro data indicate that they can directly inhibit cancer cell growth, by inducing apoptosis. Using two estrogen receptor alpha (ER) -positive breast cancer cell lines (MCF-7 and IBEP-2), and one ER-negative (MDA-MB-231), we show that ibandronate inhibits cell growth, partly through apoptosis induction, both with and without estrogenic stimulation. In addition, ibandronate does not affect neither ligand-induced ER regulation nor estrogen-induced progesterone receptor expression, indicating that bisphosphonate-treated ER+ cancer cells keep a functional form of the receptor. In this context, we show that the growth inhibition induced by classical antiestrogens, such as 4-hydroxytamoxifen and fulvestrant, is larger on cancer cells expressing ER when they are combined with ibandronate. Combination analysis identifies additive interactions between bisphosphonates and ER antagonists. Thus, our in vitro data provide for the first time a rationale for the combined use of the bisphosphonate ibandronate and antiestrogens in breast cancer patients suffering from bone metastases.
Bibilographical reference:
Fabrice
Journé, Jean-Jacques Body Laboratory
of Endocrinology and Bone Diseases, Institut Jules Bordet, Brussels,
Belgium
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