Differences in uptake and metabolism of retinoic acid between estrogen receptor-positive and -negative human breast cancer cells.
OBJECTIVE
Our previous work had shown that retinoic acid (RA) inhibits cell growth and induces apoptosis in estrogen receptor-positive (ER-positive) MCF-7 and T-47D human breast carcinoma cells, but not in ER-negative human breast carcinoma cells MB-231 and MB-453. The purpose of this work was to determine whether these differences might be due to differences in uptake and metabolism of the drug between ER-positive and ER-negative cells.


METHODS
We measured RA uptake in cultured human breast cancer cells and determined its metabolism by high-pressure liquid chromatographic analysis.


RESULTS
The two ER-positive cell lines reached maximum RA uptake at about 2 h, followed by a sharp decline, so that most RA had disappeared from the cells and from the medium by 24 h and was found as oxidation products in the culture medium. In contrast, the two ER-negative cell lines showed a pattern of lower accumulation without the sharp increase and subsequent steep decline, so that by 24 h there was more RA in these cells and their culture medium than in the RA-responsive ER-positive cells, even though at 2 h the ER-negative cells had taken up less RA than the ER-positive cells. Kinetic analysis of the uptake of RA in MCF-7 cells was consistent with rapid movement across the cell membranes and the actual rate determined by diffusion of albumin-bound retinoid to the cells.


CONCLUSIONS
This study is the first to demonstrate profound differences in RA accumulation and confirms previous results on different rates of RA metabolism between ER-positive and ER-negative human breast cancer cells. The findings reported here, therefore, may introduce additional elements to be considered in the design of new drugs for cancer chemoprevention and therapy.
Okamoto
K
K
Toho University School of Medicine, Second Department of Surgery, Tokyo, Japan.
Andreola
F
F
Chiantore
M V
MV
Dedrick
R L
RL
De Luca
L M
LM
D001692:Biological Transport; D001798:Blood Proteins / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D003470:Culture Media; D005260:Female; D006801:Humans; D007700:Kinetics; D011960:Receptors, Estrogen / Q000502:physiology*; D014212:Tretinoin / Q000493:pharmacokinetics*; D014316:Tritium; D014407:Tumor Cells, Cultured
D001798:Blood Proteins; D003470:Culture Media; D011960:Receptors, Estrogen; D014316:Tritium; D014212:Tretinoin