): Endometrial carcinoma is the most common gynecologic malignancy in the USA, and an increased risk has been associated with Tamoxifen use. The estrogen r e c eptor (ER), which activates transcription, is involved with both endometrial and breast carcinoma. ER exon deletions, including 2-8, have been shown to exist in breast cancers. The applicants' hypothesis is that human endometrial ER variants exist, and interact in a tissue-specific fashion, with growth factors (i.e., IGF-1) estrogens and antiestrogens. They will systematically evaluate these variants for both structure and function, in the presence and absence of estrogen and antiestrogens. Endometrial ER splice variants, with exon 4 and 7 deletions, have been identified in their laboratory, using RPA, RT-PCR hybridization, and DNA sequencing, RPA, RT-PCR, hybridization and DNA sequencing. RPA, RT-PCR, hybridization and DNA sequencing will be performed on premenopausal endometrium, postmenopausal endometrium, and endometrial carcinoma, in order to identify and compare the presence and quantities of ER variants. Encoded ER proteins will be identified by Western blot analysis. The function of these variants, in response to estrogen and antiestrogens including Tamoxifen, Raloxifene, and ICI compounds, will be assessed. Expression plasmids, including the wild-type and exon deletion or other variant ER cDNA's will be co-transfected with reporter plasmids including ERE enhancers (vit A2 and C3 component of complement) and an AP-1 enhancer (IGF-1). Variant ER function will be established, leading to further investigation into the effect of antiestrogens on the endometrium and the possible development of drug resistance in breast cancer patients.
| Jazaeri, A A; Nunes, K J; Dalton, M S et al. (2001) Well-differentiated endometrial adenocarcinomas and poorly differentiated mixed mullerian tumors have altered ER and PR isoform expression. Oncogene 20:6965-9 |
| Foley, E F; Jazaeri, A A; Shupnik, M A et al. (2000) Selective loss of estrogen receptor beta in malignant human colon. Cancer Res 60:245-8 |
| Jazaeri, O; Shupnik, M A; Jazaeri, A A et al. (1999) Expression of estrogen receptor alpha mRNA and protein variants in human endometrial carcinoma. Gynecol Oncol 74:38-47 |
