NORGESTREL AND GESTODENE STIMULATE BREAST-CANCER CELL-GROWTH THROUGH AN ESTROGEN-RECEPTOR MEDIATED MECHANISM

There is great concern over the long-term influence of oral contracept ives on the development of breast cancer in women. Oestrogens are know n to stimulate the growth of human breast cancer cells, and this labor atory has previously reported (Jeng & Jordan, 1991) that the 19-norpro gestin norethindrone could stimulate the proliferation of MCF-7 human breast cancer cells. We studied the influence of the 19-norprogestins norgestrel and gestodene compared to a 'non' 19-norprogestin medroxypr ogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norproges tins stimulated proliferation at a concentration of 10(-8) M, while MP A could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be bl ocked by the antioestrogen ICI 164,384, but not by the antiprogestin R U486. Transfection studies with the reporter plasmids containing an oe strogen response element or progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellu lar action of norgestrel and gestodene. The 19-norprogestins stimulate d the vitERE-CAT activity maximally at 10(-6) M, and this stimulation was inhibited by the addition of ICI 164,384. MPA did not stimulate vi tERE-CAT activity. A single base pair alteration in the palindromic se quence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the progest in activity required specific response element base sequencing. PRE15- CAT activity was stimulated by norgestrel, gestodene and MPA at concen trations well below growth stimulatory activity. This stimulation coul d be blocked by RU486. These studies suggest that the 19-norprogestins norgestrel and gestodene stimulate MCF-7 breast cancer cell growth by activating the oestrogen receptor.