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Growth factor, steroid, and steroid antagonist regulation of cyclin gene expression associated with changes in T-47D
E A Musgrove1, J A Hamilton, C S Lee
1Cancer Biology Division, Garvan Institute of Medical Research, St. Vincent's Hospital, Darlinghurst, New South Wales, Australia.
Abstract:
Cyclins and proto-oncogenes including c-myc have been implicated in eukaryotic cell cycle control. The role of cyclins in steroidal regulation of cell proliferation is unknown, but a role for c-myc has been suggested. This study investigated the relationship between regulation of T-47D breast cancer cell cycle progression, particularly by steroids and their antagonists, and changes in the levels of expression of these genes. Sequential induction of cyclins D1 (early G1 phase), D3, E, A (late G1-early S phase), and B1 (G2 phase) was observed following insulin stimulation of cell cycle progression in serum-free medium. Transient acceleration of G1-phase cells by progestin was also accompanied by rapid induction of cyclin D1, apparent within 2 h. This early induction of cyclin D1 and the ability of delayed administration of antiprogestin to antagonize progestin-induced increases in both cyclin D1 mRNA and the proportion of cells in S phase support a central role for cyclin D1 in mediating the mitogenic response in T-47D cells. Compatible with this hypothesis, antiestrogen treatment reduced the expression of cyclin D1 approximately 8 h before changes in cell cycle phase distribution accompanying growth inhibition. In the absence of progestin, antiprogestin treatment inhibited T-47D cell cycle progression but in contrast did not decrease cyclin D1 expression. Thus, changes in cyclin D1 gene expression are often, but not invariably, associated with changes in the rate of T-47D breast cancer cell cycle progression. However, both antiestrogen and antiprogestin depleted c-myc mRNA by > 80% within 2 h. These data suggest the involvement of both cyclin D1 and c-myc in the steroidal control of breast cancer cell cycle progression.
Insights
Steroids regulate breast cancer cell cycle progression by influencing cyclin D1 and c-myc gene expression. Antiprogestins and antiestrogens impact these genes, suggesting their role in controlling cell proliferation.
Area of Science:
- Molecular Biology
- Cancer Research
- Cell Biology
Background:
- Cyclins and proto-oncogenes like c-myc are key in eukaryotic cell cycle control.
- The specific role of cyclins in steroid-regulated cell proliferation remains unclear.
- A role for c-myc in this process has been previously suggested.
Purpose of the Study:
- To investigate the relationship between steroid/antagonist regulation of T-47D breast cancer cell cycle progression and gene expression changes.
- To elucidate the role of cyclin D1 and c-myc in mediating steroid-induced cell proliferation.
Main Methods:
- Sequential analysis of cyclin D1, D3, E, A, and B1 expression.
- Stimulation of T-47D cells with insulin and steroids (progestin, antiestrogen, antiprogestin).
- Measurement of gene expression (mRNA levels) and cell cycle phase distribution.
Main Results:
- Insulin stimulated sequential cyclin induction (D1, D3, E, A, B1).
- Progestin rapidly induced cyclin D1, and antiprogestin antagonized this effect, impacting S-phase entry.
- Antiestrogen reduced cyclin D1 expression prior to growth inhibition; antiprogestin depleted c-myc mRNA significantly.
Conclusions:
- Cyclin D1 plays a central role in mediating the mitogenic response to progestin in T-47D cells.
- Both cyclin D1 and c-myc are implicated in the steroidal control of breast cancer cell cycle progression.
- Changes in cyclin D1 expression are often, but not always, linked to cell cycle progression rates.