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New Treatments for ER+ Breast Cancer

Sharon B Chang, Penelope Miron, Andrew L. Kung, Alexander Miron, James D. Iglehart
Dana-Farber Cancer Institute, Boston, MA

Objective:
Estrogen receptor positive (ER+) breast cancers are treated by drugs that exploit their hormone dependence. These drugs include aromatase inhibitors and anti-estrogens like tamoxifen, but development of resistance can limit their use. Rapamycin, a bacterial product, may become an important adjunct to treatment; it inhibits the mammalian Target of Rapamycin (mTOR), which controls cell growth/proliferation. Furthermore, rapamycin is highly effective against ER+ breast cancer cell lines. We investigated the role of rapamycin/mTOR inhibition in E2-driven proliferation and E2-stimulated signal transduction.
Design:
Proliferation assays; Western and Northern blot analyses of MCF-7 breast cancer cells.
Setting:
Cancer institute.
Patients:
None.
Interventions:
Treatment with rapamycin, 4-hydroxytamoxifen (4-OHT), and mTOR RNA interference (RNAi).
Main Outcome Measures:
Proliferation--MTS assay; phosphorylation of mTOR substrate S6K1; expression of E2-responsive gene pS2 transcript.
Results:
Rapamycin inhibited E2-driven proliferation of MCF-7 cells, and combinations of rapamycin and 4-OHT had additive inhibitory effects. Treatment of MCF-7 cells with E2 increased phosphorylation of S6K1 within 15 minutes; this phosphorylation was inhibited by rapamycin pretreatment and by mTOR RNAi. Rapamycin also inhibited induction of pS2 transcript by E2.
Conclusions:
Rapamycin, alone and in combination with 4-OHT, potently inhibits E2 dependent proliferation of MCF-7 cells. mTOR appears to play a role in both early and later E2-stimulated signal transduction. These results suggest that inhibitors of mTOR such as rapamycin may be a powerful addition to the treatment of ER+ breast cancers.

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