Phenotypic differentiation of human breast cancer cells by 1,3 cyclic propanediol phosphate.
Breast cancer cells in their virulent undifferentiated state are characterized by lack of functional estrogen receptors (ER) and/or progesterone receptors (PR) as well as relatively low levels of other normal differentiation markers such as milk proteins and lipid droplets. To date, no method for in situ elevation of the state of differentiation of breast cancer cells has yet been proven effective in patients. We have recently shown that 1,3 cyclic propanediol phosphate (1,3 cPP), an analog of 1,3 cyclic glycerophosphate (1,3 cGP), can promote morphological, neuronal-like differentiation in pheochromocytoma-12 cells in vitro. In view of this observation, we tested the potential of 1,3 cPP to elevate the state of cellular differentiation of the human breast cancer cell lines MCF-7 (ER(+)) and HCC1954 (ER(-)), as characterized by the expression of steroid receptors, casein kinase, lipid droplet histology and signal-transduction gene profiles. In the range of 5-100 microM 1,3 cPP the in vitro expression of ER-alpha, PR and casein kinase increased by approximately 2-fold while the mRNA transcription increased by 2-6-fold. Moreover, following 9-12 days of incubation with 1,3 cPP, HCC1954 cells exhibited a significant increase in the production of lipid droplets as observed by Oil Red O staining. The in vivo effect of 1,3 PP on MCF-7 xenografted into nude mice was also determined. After 4 biweekly i.p. injections of 0.5 mg 1,3 cPP per mouse, tumors in the 1,3 cPP treated virtually did not grow at all while the tumors in the control group grew rapidly. Based on these findings, we propose that this novel differentiating compound has the potential to transform the malignant tumor phenotype into a near-normal phenotype, as well as to sensitize the tumor cells to anti-estrogen therapy via upgrading the status of steroid hormone receptors.
Adan
Yosef
Y
Department of Biological Chemistry, The Weizmann Institute of Science, Rehovot 76100, Israel.
Goldman
Yechiel
Y
Haimovitz
Rachel
R
Mammon
Keren
K
Eilon
Tali
T
Tal
Saar
S
Tene
Anat
A
Karmel
Yael
Y
Shinitzky
Meir
M
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D001391:Azo Compounds / Q000494:pharmacology; D014408:Biomarkers, Tumor; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000473:pathology*; D047388:Casein Kinases; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D004396:Coloring Agents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D047628:Estrogen Receptor alpha; D005091:Exons; D005260:Female; D006801:Humans; D050356:Lipid Metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D011409:Propylene Glycols / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014407:Tumor Cells, Cultured
C474998:1,3-cyclic propanediol phosphate; D000970:Antineoplastic Agents; D001391:Azo Compounds; D014408:Biomarkers, Tumor; D004396:Coloring Agents; D047628:Estrogen Receptor alpha; D011409:Propylene Glycols; D012333:RNA, Messenger; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D011494:Protein Kinases; D047388:Casein Kinases; C011049:oil red O