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Development and Therapeutic Options for the Treatment of Raloxifene-Stimulated Breast Cancer in Athymic Mice
Ist Teil von
Clinical cancer research, 2006-04, Vol.12 (7), p.2255-2263
Ort / Verlag
Philadelphia, PA: American Association for Cancer Research
Erscheinungsjahr
2006
Quelle
MEDLINE
Beschreibungen/Notizen
Purpose: Selective estrogen receptor modulators (SERM) are used for the treatment and prevention of breast cancer (tamoxifen) and
osteoporosis (raloxifene). Mechanisms of tamoxifen-resistance in breast cancer are incompletely understood but current research
is focused on crosstalk between growth factor receptors and the estrogen receptor α (ERα) pathway. There is increasing clinical
use of raloxifene for the treatment of osteoporosis, but the widespread use of this SERM will have consequences for the treatment
of breast cancer in raloxifene-exposed women.
Experimental Design: We took the strategic step of developing a raloxifene-resistant tumor (MCF-7RALT) model in vivo and investigating the mechanisms responsible for resistance.
Results: MCF-7RALT tumors exhibited phase I SERM resistance, growing in response to SERMs and 17β-estradiol. Epidermal growth factor
receptor/HER1 and HER2/ neu mRNAs were increased in MCF-7RALT tumors. The HER2/ neu blocker, trastuzumab, but not the epidermal growth factor receptor blocker, gefitinib, decreased the growth of MCF-7RALT
tumors in vivo . Consequently, trastuzumab decreased prosurvival/proliferative proteins: phospho-HER2/ neu , total HER2/ neu , phospho-Akt (protein kinase B), glycogen synthetase kinase-3, cyclin D1, and the antiapoptotic protein X chromosome-linked
inhibitor of apoptosis, whereas increasing the proapoptotic protein, caspase-7, in raloxifene-treated MCF-7RALT tumors. Interestingly,
ERα protein was overexpressed in untreated MCF-7RALT tumors and hyperactivated in cells derived from these tumors. Only fulvestrant
completely inhibited the growth and ERα activity of MCF-7RALT tumors. The coactivator of ERα, amplified in breast cancer-1
protein was modestly increased in the raloxifene-treated MCF-7RALT tumors and increased both basal and estradiol-induced activity
of ERα in cells derived from the MCF-7RALT tumors.
Conclusions: These results suggest that overexpression and increased activity of HER2/ neu might be responsible for the development of raloxifene-resistant breast cancer. The results also suggest that increased expression
of basal activity of ERα could contribute to the hypersensitivity of MCF-7RALT tumors in response to estradiol because only
fulvestrant blocked growth and ERα activity.