Resistance to Tamoxifen: A Consequence of Altered p27Kipl Regulation During Breast Cancer Progression
Abstract
This grant addresses the molecular mechanisms of resistance to the anti-estrogen, Tamoxifen, in breast cancers. Both estrogens and antiestrogens influence the cell cycle during the GI phase. In breast tumors, loss of the cdk inhibitor, p27, is associated with a poor prognosis and with steroid resistance. We postulate that altered p27 degradation in breast cancer may contribute to resistance to antiestrogen therapy. In the last year, we have assayed cell cycle effects of estradiol in the ER+ breast cancer cell line, MCF-7. MCF-7 arrests in G1 upon removal of estradiol or on addition of Tamoxifen. Upon re-addition of estradiol, cells re-enter the cell cycle with onset of S phase by 12 hours and loss of both p21 and p27 proteins. Cyclin D1 associated kinase activity rose transiently in early G1. Activation of cyclin E/cdk2 kinase in mid-late G1 was accompanied by loss of cyclin E-associated p21 and p27. The requirement for p27 in the quiescence induced by estradiol depletion was investigated using antisense p27 oligonucleotides. Introduction of the antisense oligonucleotides into quiescent estradiol depleted MCF-7 cells reduced p27 levels five fold. Despite the continued absence of estradiol, the p27 antisense treated group entered into S phase, with an S phase fraction of 28 % at 34 hours post-transfection, while control cells remained arrested. Thus, the loss of p27 was sufficient to mimic the effect of estradiol on G1-to-S phase progression in MCF-7 cells. These data suggest that loss of p27 is critical for estradiol dependant stimulation of breast cancer proliferation and an increase in p27 is essential for cell cycle arrest following an inhibition of estradiol signaling. Ongoing studies address how these effects are altered in steroid resistant breast cancer.
Document Details
- Document Type
- Technical Report
- Publication Date
- Jun 01, 1999
- Accession Number
- ADA382749
Entities
People
- Joyce M Slingerland