Progesterone, in addition to estrogen, induces cyclin D1 expression in the murine mammary epithelial cell, in vivo.

Previous investigations, in vitro, have demonstrated that progestins can induce the transcription of the cell cycle regulator, cyclin D1, thereby suggesting that cyclin D1 may mediate, at the molecular level, the proposed mitogenic effects of progesterone during mammary epithelial cell proliferation. To extend these initial studies into an in vivo context, comparative cyclin D1 Northern and immunohistochemical analyses were performed on mammary gland tissue isolated from wild type (WT) females as well as from the recently reported progesterone receptor knockout (PRKO) mouse model. Northern analysis revealed that estrogen induced cyclin D1 expression, 5- to 7-fold over control levels, both in the WT and PRKO female. Immunohistochemistry demonstrated that, for both test groups, the number of mammary epithelial cells expressing cyclin D1 increased significantly as compared with control values, in response to estrogen. In the case of estrogen plus progesterone treatment, Northern analysis revealed that, in the WT gland, cyclin D1 transcription increased approximately 3-fold over estrogen induced levels, an increase that was paralleled by an equivalent increase in the number of mammary epithelial cells expressing cyclin D1. Conversely, under the same hormone regimen, the PRKO mammary gland did not exhibit a further increase in cyclin D1 induction over estrogen only levels. Finally, these studies not only demonstrate that in the mammary epithelial cell, both estrogen and progesterone can induce the expression of cyclin D1 but also show that this induction correlates with mammary gland proliferation in the mouse.

[1]  B. O’Malley,et al.  Mammary gland development is mediated by both stromal and epithelial progesterone receptors. , 1997, Molecular endocrinology.

[2]  R. Bernards,et al.  CDK-Independent Activation of Estrogen Receptor by Cyclin D1 , 1997, Cell.

[3]  R. Sutherland,et al.  Antiprogestin inhibition of cell cycle progression in T-47D breast cancer cells is accompanied by induction of the cyclin-dependent kinase inhibitor p21. , 1997, Molecular endocrinology.

[4]  J. Harper,et al.  Mammalian p50Cdc37 is a protein kinase-targeting subunit of Hsp90 that binds and stabilizes Cdk4. , 1996, Genes & development.

[5]  L. Altucci,et al.  17beta-Estradiol induces cyclin D1 gene transcription, p36D1-p34cdk4 complex activation and p105Rb phosphorylation during mitogenic stimulation of G(1)-arrested human breast cancer cells. , 1996, Oncogene.

[6]  J. S. Foster,et al.  Estrogen regulates activity of cyclin-dependent kinases and retinoblastoma protein phosphorylation in breast cancer cells. , 1996, Molecular endocrinology.

[7]  M. Pike,et al.  Experiments on proliferation of normal human breast tissue in nude mice do not show that progesterone does not stimulate breast cells. , 1996, Endocrinology.

[8]  G. Stamp,et al.  Mice lacking cyclin D1 are small and show defects in eye and mammary gland development. , 1995, Genes & development.

[9]  D. Medina,et al.  Mouse mammary hyperplasias and neoplasias exhibit different patterns of cyclins D1 and D2 binding to cdk4. , 1995, Carcinogenesis.

[10]  B. O’Malley,et al.  Mice lacking progesterone receptor exhibit pleiotropic reproductive abnormalities. , 1995, Genes & development.

[11]  S. Elledge,et al.  Cyclin D1 provides a link between development and oncogenesis in the retina and breast , 1995, Cell.

[12]  D. Medina,et al.  Cell cyclins and cyclin-dependent kinase activities in mouse mammary tumor development. , 1995, Carcinogenesis.

[13]  A. Howell,et al.  The proliferation of normal human breast tissue implanted into athymic nude mice is stimulated by estrogen but not progesterone. , 1995, Endocrinology.

[14]  J. A. Hamilton,et al.  Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D human breast cancer cell cycle progression. , 1993, Molecular and cellular biology.

[15]  Richard A. Ashmun,et al.  Colony-stimulating factor 1 regulates novel cyclins during the G1 phase of the cell cycle , 1991, Cell.

[16]  C. Clarke,et al.  Progestin regulation of cellular proliferation. , 1990, Endocrine reviews.

[17]  S. Haslam Progesterone effects on deoxyribonucleic acid synthesis in normal mouse mammary glands. , 1988, Endocrinology.

[18]  S. Robinson,et al.  Reversal of the antitumor effects of tamoxifen by progesterone in the 7,12-dimethylbenzanthracene-induced rat mammary carcinoma model. , 1987, Cancer research.

[19]  C. Welsch Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. , 1985, Cancer research.

[20]  S. Hamamoto,et al.  Stimulation of mammary epithelial cell growth in vitro: interaction of epidermal growth factor and mammogenic hormones. , 1985, Endocrinology.

[21]  G. Bradford,et al.  Plasma progesterone during pregnancy in the mouse. , 1974, Endocrinology.

[22]  D R Griffin,et al.  Letters to the editor. , 1974, Science.