Rapamycin inhibits proliferation of estrogen-receptor-positive breast cancer cells.
BACKGROUND
Estrogen-receptor (ER)-positive breast cancers comprise the majority of sporadic breast cancers. Although 50% respond to antihormonal treatment, both primary and acquired resistance limit the utility of this therapy, and other agents are needed. Rapamycin, an inhibitor of the mammalian Target of Rapamycin (mTOR), possesses antitumor activity against many tumors including breast tumors, and particularly against ER-positive breast cancer cell lines. The sensitivity of these cells to rapamycin has been attributed to activation of the PI3K/Akt/mTOR pathway by nongenomic ER signaling. The purpose of this study was to evaluate the efficacy of rapamycin against ER-positive breast cancer, particularly under 17beta-estradiol (E2)-dependent conditions, and to investigate mechanisms of rapamycin-sensitivity in ER-positive cells.


METHODS
Breast cancer cell lines were tested for sensitivity to rapamycin. Antiproliferative effects of rapamycin, alone and in combination with tamoxifen, were assessed under E2-dependent conditions. Western blot analysis was used to detect activation of mTOR by nongenomic ER signaling.


RESULTS
Rapamycin effectively inhibits proliferation of the ER-positive MCF-7 cell line. In our system, this sensitivity is probably not due to nongenomic ER activation of the PI3K/Akt/mTOR pathway; rapid stimulation of mTOR occurred nonspecifically after medium replacement, and addition of E2 stimulated mTOR only after 1 h. Combining rapamycin and tamoxifen under E2-dependent conditions yielded additive/synergistic effects at effective concentrations.


CONCLUSIONS
These results suggest that rapamycin may be an effective treatment for ER-positive breast cancer, either alone or in combination with tamoxifen, and also may be a potential therapy for tamoxifen-resistant cancers.
Chang
Sharon B
SB
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. sharon.chang@ucdmc.ucdavis.edu <sharon.chang@ucdmc.ucdavis.edu>
Miron
Penelope
P
Miron
Alexander
A
Iglehart
J Dirk
JD
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D004958:Estradiol / Q000494:pharmacology; D006801:Humans; D010766:Phosphorylation / Q000187:drug effects; D011494:Protein Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism*; D019893:Ribosomal Protein S6 Kinases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases; D013629:Tamoxifen / Q000494:pharmacology
D000903:Antibiotics, Antineoplastic; D018931:Antineoplastic Agents, Hormonal; D011960:Receptors, Estrogen; D013629:Tamoxifen; D004958:Estradiol; D011494:Protein Kinases; C546842:MTOR protein, human; D019893:Ribosomal Protein S6 Kinases; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus