Effects of raloxifene on breast cancer cell migration and  invasion through the actin cytoskeleton.
Raloxifene (RAL) is a selective oestrogen receptor modulator (SERM) approved for the prevention and treatment of osteoporosis and for the prevention of breast cancer in postmenopausal women. However, little is known on the effects of this SERM on breast cancer cell metastasis, which is the main cause of morbidity and death. Cell movement is critical for local progression and distant metastasis of cancer cells. These processes rely on the dynamic control of the actin cytoskeleton and of cell membrane morphology. The aim of the present study was to characterize the effects of RAL or of 17beta-estradiol (E2) plus RAL on oestrogen receptor (ER) positive T47-D breast cancer cell cytoskeletal remodelling, migration and invasion. Our findings show that, when given alone, RAL induces a weak actin cytoskeleton remodelling in breast cancer cells, with the formation of specialized cell membrane structures implicated in cell motility. However, in the presence of physiological amounts of estradiol, which potently drives breast cancer cell cytoskeletal remodelling and motility, RAL displays a powerful inhibitory effect on oestrogen-promoted cell migration and invasion. These actions are plaid through an interference of RAL with an extra-nuclear signalling cascade involving G proteins and the RhoA-associated kinase, ROCK-2, linked to the recruitment of the cytoskeletal controller, moesin. Hence, in the presence of estradiol, RAL acts as an ER antagonist. These results highlight a novel mechanism of action of the SERM raloxifene that might be important for the interference of breast cancer progression or metastasis induced by oestrogens in postmenopausal women.
Flamini
Marina Ines
MI
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Fu
Xiao-Dong
XD
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Sanchez
Angel Matias
AM
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Giretti
Maria Silvia
MS
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Garibaldi
Silvia
S
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Goglia
Lorenzo
L
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Pisaneschi
Silvia
S
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Tosi
Veronica
V
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Genazzani
Andrea Riccardo
AR
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
Simoncini
Tommaso
T
Molecular and Cellular Gynecological Endocrinology Laboratory (MCGEL), Department of Reproductive Medicine and Child Development, University of Pisa, Pisa, Italy.
D000199:Actins / Q000378:metabolism*; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D006801:Humans; D009361:Neoplasm Invasiveness / Q000517:prevention & control*; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D020849:Raloxifene Hydrochloride / Q000494:pharmacology*
D000199:Actins; D020849:Raloxifene Hydrochloride
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