Catherino W H, Jeng M H, Jordan V C
Department of Human Oncology, University of Wisconsin Comprehensive Cancer Center, Madison 53792.
Br J Cancer. 1993 May;67(5):945-52. doi: 10.1038/bjc.1993.175.
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.
人们高度关注口服避孕药对女性乳腺癌发展的长期影响。已知雌激素会刺激人乳腺癌细胞的生长，并且本实验室之前曾报道（Jeng和Jordan，1991年）19-去甲孕酮炔诺酮可刺激MCF-7人乳腺癌细胞的增殖。我们研究了19-去甲孕酮炔诺孕酮和孕二烯酮与“非”19-去甲孕酮醋酸甲羟孕酮（MPA）相比对MCF-7细胞增殖的影响。19-去甲孕酮在浓度为10^(-8) M时刺激增殖，而MPA在高达3×10^(-6) M的浓度下都无法刺激增殖。19-去甲孕酮的刺激活性可被抗雌激素ICI 164,384阻断，但不能被抗孕激素RU486阻断。使用含有雌激素反应元件或孕激素反应元件（vitERE-CAT、pS2ERE-CAT和PRE15-CAT）的报告质粒进行转染研究，以确定炔诺孕酮和孕二烯酮的细胞内作用。19-去甲孕酮在10^(-6) M时最大程度地刺激vitERE-CAT活性，并且这种刺激会因添加ICI 164,384而受到抑制。MPA不会刺激vitERE-CAT活性。vitERE回文序列中的单个碱基对改变（导致pS2ERE）导致19-去甲孕酮使CAT表达大幅下降，这表明孕激素活性需要特定的反应元件碱基序列。PRE15-CAT活性在远低于生长刺激活性的浓度下被炔诺孕酮、孕二烯酮和MPA刺激。这种刺激可被RU486阻断。这些研究表明，19-去甲孕酮炔诺孕酮和孕二烯酮通过激活雌激素受体来刺激MCF-7乳腺癌细胞生长。
