5,6-Dihydro-5'-azacytidine (DHAC) affects estrogen sensitivity in estrogen-refractory human breast carcinoma cell
E Izbicka1, K K Davidson, R A Lawrence
1Institute for Drug Development, Cancer Therapy and Research Center, Nordan Colon Cancer Laboratory, San Antonio, Texas 78229, USA. eizbicka@saci.org
Background:
There is little effective therapy for patients with hormone-refractory breast cancer. Hormone resistance is frequently due to the transcriptional inactivation of the estrogen receptor (ER) gene. We determined the effect of DHAC, a cytosine DNA methyltransferase (CMT) inhibitor, on the estrogen sensitivity in three human breast carcinoma cell lines with intermediate to low levels of estrogen receptor (ER) expression: MCF7 (adriamycin-sensitive), MCF7M/Adr (adriamycin-resistant), and MDA-435, and one ER+ cell line, ZR75-1.
Materials And Methods:
Cells maintained in culture were exposed to DHAC or vehicle continuously for 14 days, then exposed to estradiol or tamoxifen and counted on day 21.
Results:
Exposure to DHAC did not affect estrogen sensitivity in ZR-75-1 and MCF7M/Adr cells. DHAC treatment of MCF7 and MDA-435 cells resulted in significant (p < 0.05) growth stimulation in response to estrogen at 10(-6) M, and to growth modulation by tamoxifen at 10(-5) to 10(-7) M.
Conclusions:
These data suggest that DHAC can restore the estrogen sensitivity in ER-breast cancer. Thus, DHAC and other novel CMT inhibitors may have a clinical application in treating estrogen-refractory breast cancer patients by restoring the estrogen sensitivity and allowing these patients to respond again to conventional therapy with estrogen antagonists.
Insights
DHAC, a DNA methyltransferase inhibitor, may restore estrogen sensitivity in estrogen receptor-negative breast cancer. This could allow patients with estrogen-refractory breast cancer to respond to conventional therapies.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Hormone-refractory breast cancer lacks effective therapies, often due to estrogen receptor (ER) gene inactivation.
- Cytosine DNA methyltransferase (CMT) inhibitors are being investigated for therapeutic potential.
Purpose of the Study:
- To determine the effect of DHAC, a CMT inhibitor, on estrogen sensitivity in human breast cancer cell lines.
- To evaluate DHAC's potential to restore estrogen sensitivity in ER-negative breast cancer models.
Main Methods:
- Human breast cancer cell lines (MCF7, MCF7M/Adr, MDA-435, ZR75-1) were cultured.
- Cells were continuously exposed to DHAC or vehicle for 14 days.
- Estradiol or tamoxifen treatment and cell counting were performed on day 21.
Main Results:
- DHAC did not alter estrogen sensitivity in ZR-75-1 and MCF7M/Adr cells.
- DHAC treatment significantly enhanced estrogen sensitivity in MCF7 and MDA-435 cells (p < 0.05).
- Tamoxifen modulated growth in DHAC-treated MCF7 and MDA-435 cells.
Conclusions:
- DHAC can restore estrogen sensitivity in ER-negative breast cancer cells.
- Novel CMT inhibitors like DHAC may offer clinical applications for estrogen-refractory breast cancer.
- DHAC may re-sensitize patients to conventional estrogen antagonist therapies.
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