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Estrogen and progestin regulation of cell cycle progression
R L Sutherland1, O W Prall, C K Watts
1Cancer Research Program, Garvan Institute of Medical Research, St. Vincent's Hospital, Sydney, NSW, Australia. r.sutherland@garvan.unsw.edu.au
Abstract:
Estrogens and progesterone, acting via their specific nuclear receptors, are essential for normal mammary gland development and differentiated function. The molecular mechanisms through which these effects are mediated are not well defined, although significant recent progress has been made in linking steroid hormone action to cell cycle progression. This review summarizes data identifying c-myc and cyclin D1 as major downstream targets of both estrogen- and progestin-stimulated cell cycle progression in human breast cancer cells. Additionally, estrogen induces the formation of high specific activity forms of the cyclin E-Cdk2 enzyme complex lacking the cyclin-dependent kinase (CDK)3 inhibitor, p21. The delayed growth inhibitory effects of progestins, which are likely to be prerequisites for manifestation of their function in differentiation, also involve decreases in cyclin D1 and E gene expression and recruitment of CDK inhibitors into cyclin D1-Cdk4 and cyclin E-Cdk2 complexes. Thus estrogens and progestins affect CDK function not only by effects on cyclin abundance but also by regulating the recruitment of CDK inhibitors and, as yet undefined, additional components which determine the activity of the CDK complexes. These effects of estrogens and progestins are likely to be major contributors to their regulation of mammary epithelial cell proliferation and differentiation.
Insights
Estrogens and progestins regulate breast cancer cell cycle progression by targeting key proteins like c-myc and cyclins. They influence cell proliferation and differentiation through complex interactions with cyclin-dependent kinases and their inhibitors.
Area of Science:
- Endocrinology
- Molecular Biology
- Cancer Research
Background:
- Estrogens and progesterone are crucial for mammary gland development and function.
- Steroid hormone mechanisms in cell cycle regulation are not fully understood.
- Recent advances link steroid hormone action to cell cycle progression.
Purpose of the Study:
- To review molecular mechanisms of estrogen and progestin action on cell cycle progression.
- To identify downstream targets of steroid hormone-stimulated cell cycle progression.
- To elucidate the role of cyclin-dependent kinases (CDKs) and inhibitors in mediating these effects.
Main Methods:
- Review of existing scientific literature and data.
- Analysis of gene expression and protein complex formation.
- Focus on human breast cancer cell models.
Main Results:
- Estrogen and progestin stimulate cell cycle progression by targeting c-myc and cyclin D1.
- Estrogen induces active cyclin E-Cdk2 complexes lacking p21.
- Progestins decrease cyclin D1 and E expression and increase CDK inhibitor recruitment.
Conclusions:
- Estrogens and progestins modulate CDK activity via cyclin abundance and CDK inhibitor recruitment.
- These hormonal effects are critical for regulating mammary epithelial cell proliferation and differentiation.
- Understanding these pathways is key to breast cancer therapy and understanding development.