Inhibition of the phosphatidylinositol 3-kinase/Akt pathway improves response of long-term estrogen-deprived breast cancer xenografts to antiestrogens.
OBJECTIVE
Aromatase inhibitors that block the synthesis of estrogen are proving to be superior to antiestrogens and may replace tamoxifen as first-line treatment for postmenopausal estrogen receptor (ER)-positive breast cancer patients. However, acquisition of resistance to all forms of treatments is inevitable and a major clinical concern. In this study, we have investigated the effects of long-term estrogen deprivation in the breast cancer xenograft model and whether sensitivity to antiestrogens can be restored in vivo. We also compared whether combining wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone.


METHODS
Long-term estrogen-deprived aromatase-transfected human ER-positive breast cancer cells (UMB-1Ca) were grown as tumors in ovariectomized athymic nude mice. Twelve weeks after inoculation, when tumors reached 300 mm(3), animals were grouped and injected with vehicle, Delta(4)A, letrozole, tamoxifen, fulvestrant, wortmannin, tamoxifen plus wortmannin, and wortmannin plus fulvestrant. Tumor volumes were measured weekly.


RESULTS
Tumors of UMB-1Ca cells grew equally well with and without androstenedione, indicating the ability of the cells to proliferate in the absence of estrogen. The combination of wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone. The combination of wortmannin plus fulvestrant was the most effective treatment that maintained tumor regression for a prolonged time.


CONCLUSIONS
These results suggest that blocking both ER and growth factor receptor pathways could provide effective control over tumor growth of long-term estrogen-deprived human breast cancers.
Sabnis
Gauri
G
Department of Pharmacology and Experimental Therapeutics, University of Maryland Baltimore and University of Maryland Greenebaum Cancer Center, Baltimore, Maryland, USA.
Goloubeva
Olga
O
Jelovac
Danijela
D
Schayowitz
Adam
A
Brodie
Angela
A
D000730:Androstadienes / Q000627:therapeutic use; D000735:Androstenedione / Q000627:therapeutic use; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D047072:Aromatase Inhibitors / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D045744:Cell Line, Tumor; D020847:Estrogen Receptor Modulators / Q000627:therapeutic use*; D047628:Estrogen Receptor alpha / Q000378:metabolism; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D009570:Nitriles / Q000627:therapeutic use; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors*; D013629:Tamoxifen / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D000077191:Wortmannin
D000730:Androstadienes; D047072:Aromatase Inhibitors; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D009570:Nitriles; D000081082:Phosphoinositide-3 Kinase Inhibitors; D014230:Triazoles; D013629:Tamoxifen; D000735:Androstenedione; D000077289:Letrozole; D051057:Proto-Oncogene Proteins c-akt; D000077191:Wortmannin