CONICET | Buscador de Institutos y Recursos Humanos

Background: The role of progestins used in hormone replacement therapy on breast cancer development is controversial. Little is known on the effects of progestins on breast cancer progression and metastasis and on possible differences between progestins. Objective: We investigated the effects of progesterone (P), medroxyprogesterone acetate (MPA), drospirenone (DRSP) and nestorone (NES) alone or with 17 -estradiol (E2) on T47-D breast cancer cell migration and invasion and we characterized the signaling steps recruited by these progestins. Results: Breast cancer cell horizontal migration and invasion of three-dimensional matrices are enhanced by all the investigated progestins, but differences are found in terms of potency, with MPA being most active and DRSP being markedly less active. This is related to the differential ability of the progestins to activate the actin-binding protein moesin, leading to distinct effects on actin cytoskeleton remodeling and on the formation of cell membrane structures that mediate cell movement. The addition of E2 to any of these progestins enhances moesin activation, actin cytoskeleton remodeling, cell migration and invasion of breast cancer cells over that achieved by each progestin alone. Conclusions: These results imply that P, MPA, DRSP and NES alone or in combination with E2 enhance the tendency of breast cancer cells to move in the surrounding environment. However, these progestins show different potencies and to some extent use distinct intracellular intermediates to drive moesin activation and actin remodeling. These findings support the concept that each acts differently on breast cancer cells, which may have relevant clinical implications.

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