There is great concern over the long-term influence of
oral contraceptives on the development of
breast cancer in women. Oestrogens are known to stimulate the growth of human
breast cancer cells, and this laboratory has previously reported (Jeng & Jordan, 1991) that the 19-norprogestin
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
medroxyprogesterone acetate (MPA) on MCF-7 cell proliferation. The 19-norprogestins stimulated proliferation at a concentration of 10(-8) M, while MPA could not stimulate proliferation at concentrations as great as 3 x 10(-6) M. The stimulatory activity of the 19-norprogestins could be blocked by the antioestrogen ICI 164,384, but not by the antiprogestin
RU486. Transfection studies with the reporter plasmids containing an oestrogen response element or
progesterone response element (vitERE-CAT, pS2ERE-CAT, and PRE15-CAT) were performed to determine the intracellular action of
norgestrel and
gestodene. The 19-norprogestins stimulated 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 vitERE-CAT activity. A single base pair alteration in the palindromic sequence of vitERE (resulting in the pS2ERE) led to a dramatic decrease in CAT expression by the 19-norprogestins, suggesting that the
progestin activity required specific response element base sequencing. PRE15-CAT activity was stimulated by
norgestrel,
gestodene and MPA at concentrations well below growth stimulatory activity. This stimulation could 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.