This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Erenburg, I. Articles by Ossowski, L. Search for Related Content PubMed PubMed Citation Articles by Erenburg, I. Articles by Ossowski, L.

Loss of an Estrogen Receptor Isoform (ER3) in Breast Cancer and the Consequences of Its Reexpression: Interference with Estrogen-Stimulated Properties of Malignant Transformation

Department of Cell Biology (I.E., B.S., L.O.) Rochelle Belfer Chemotherapy Foundation Laboratory (I.E., R.M.L., L.O) Department of Medicine Department of Obstetrics and Gynecology (B.S.) Mount Sinai School of Medicine New York, New York 10029

Comparison of mRNA ratios of a non-DNA-binding estrogen receptor (ER) isoform, missing exon 3 (ER3), to the full-length ER, in normal breast epithelium to that in primary breast cancers and breast cancer cell lines revealed a 30-fold reduction of this ratio in cancer cells (P < 0.0001). To test what functions may have been affected by the loss of ER3, stable clones of MCF-7 cells expressing ectopic ER3 protein, at the range of physiological ER, were generated. In vector-transfected controls the ER3-mRNA and protein were less than 10% while in the ER3-expressing clones, ER3-mRNA and protein ranged from 36–76% of the total ER. Estrogen (E₂) stimulated the expression of pS2-mRNA in pMV7 vector control cells, but the stimulation was reduced by up to 93% in ER3-expressing clones. In addition, several properties associated with the transformed phenotype were also strongly affected when ER3 protein was reexpressed. Compared with vector-transfected control cells, the saturation density of the ER3-expressing clones was reduced by 50–68%, while their exponential growth rate was only slightly (14.5 ± 5%) lower. The in vivo invasiveness of the ER3-expressing cells was significantly reduced (P = 0.007) by up to 79%. E₂ stimulated anchorage-independent growth of the pMV7 vector control cells, but reduced it to below baseline levels in ER3 clones. The reduction of the pS2 response to E₂ in the ER3-expressing clones and the E₂ block of anchorage-independent growth to below baseline were more pronounced than expected from the dominant negative function of ER3. These observations suggest that E₂ may activate an additional ER3-dependent inhibitory pathway. The drastic reduction of ER3 to ER ratio in breast cancer, and the fact that when present in breast cancer cells this isoform leads to a suppression, rather than enhancement, of the transformed phenotype by E₂ suggests that the regulation of ER-mRNA splicing may need to be altered for the breast carcinogenesis to proceed.

This article has been cited by other articles:

				M. Maynadier, J.-M. Ramirez, A.-M. Cathiard, N. Platet, D. Gras, M. Gleizes, M. S. Sheikh, P. Nirde, and M. Garcia Unliganded estrogen receptor {alpha} inhibits breast cancer cell growth through interaction with a cyclin-dependent kinase inhibitor (p21WAF1) FASEB J, March 1, 2008; 22(3): 671 - 681. [Abstract] [Full Text] [PDF]

				T. A. Ishunina, D. F. Swaab, and D. F. Fischer Estrogen Receptor-{alpha} Splice Variants in the Medial Mamillary Nucleus of Alzheimer's Disease Patients: Identification of a Novel MB1 Isoform J. Clin. Endocrinol. Metab., June 1, 2005; 90(6): 3757 - 3765. [Abstract] [Full Text] [PDF]

				M. H. Herynk and S. A. W. Fuqua Estrogen Receptor Mutations in Human Disease Endocr. Rev., December 1, 2004; 25(6): 869 - 898. [Abstract] [Full Text] [PDF]

				J. M. Garcia Pedrero, P. Zuazua, C. Martinez-Campa, P. S. Lazo, and S. Ramos The Naturally Occurring Variant of Estrogen Receptor (ER) ER{Delta}E7 Suppresses Estrogen-Dependent Transcriptional Activation by Both Wild-Type ER{alpha} and ER{beta} Endocrinology, July 1, 2003; 144(7): 2967 - 2976. [Abstract] [Full Text] [PDF]

				C. Tiffoche, C. Vaillant, D. Schausi, and M.-L. Thieulant Novel Intronic Promoter in the Rat ER{alpha} Gene Responsible for the Transient Transcription of a Variant Receptor Endocrinology, September 1, 2001; 142(9): 4106 - 4119. [Abstract] [Full Text] [PDF]

				C. Pasqualini, D. Guivarc'h, J.-V. Barnier, B. Guibert, J.-D. Vincent, and P. Vernier Differential Subcellular Distribution and Transcriptional Activity of {{Sigma}}E3, {{Sigma}}E4, and {{Sigma}}E3-4 Isoforms of the Rat Estrogen Receptor-{{alpha}} Mol. Endocrinol., June 1, 2001; 15(6): 894 - 908. [Abstract] [Full Text] [PDF]

				N. Platet, S. Cunat, D. Chalbos, H. Rochefort, and M. Garcia Unliganded and Liganded Estrogen Receptors Protect against Cancer Invasion via Different Mechanisms Mol. Endocrinol., July 1, 2000; 14(7): 999 - 1009. [Abstract] [Full Text]

				A. Bollig and R. J. Miksicek An Estrogen Receptor-{alpha} Splicing Variant Mediates Both Positive and Negative Effects on Gene Transcription Mol. Endocrinol., May 1, 2000; 14(5): 634 - 649. [Abstract] [Full Text]

				F. Pakdel, R. Metivier, G. Flouriot, and Y. Valotaire Two Estrogen Receptor (ER) Isoforms with Different Estrogen Dependencies Are Generated from the Trout ER Gene Endocrinology, February 1, 2000; 141(2): 571 - 580. [Abstract] [Full Text] [PDF]

				M. L. O’Brien, K. Park, Y. In, and O.-K. Park-Sarge Characterization of Estrogen Receptor-{beta} (ER{beta}) Messenger Ribonucleic Acid and Protein Expression in Rat Granulosa Cells Endocrinology, October 1, 1999; 140(10): 4530 - 4541. [Abstract] [Full Text]

				C. Pasqualini, D. Guivarc’h, Y. v. Boxberg, F. Nothias, J.-D. Vincent, and P. Vernier Stage- and Region-Specific Expression of Estrogen Receptor {alpha} Isoforms during Ontogeny of the Pituitary Gland Endocrinology, June 1, 1999; 140(6): 2781 - 2789. [Abstract] [Full Text]

				R. L. Balleine, S. M. N. Hunt, and C. L. Clarke Coexpression of Alternatively Spliced Estrogen and Progesterone Receptor Transcripts in Human Breast Cancer J. Clin. Endocrinol. Metab., April 1, 1999; 84(4): 1370 - 1377. [Abstract] [Full Text]