Presence of Alternatively Spliced-Estrogen Receptor mRNA Variants in Normal Human Uterine Endometrium and Endometrial Cancer.

Abstract

Abstract. Presence of alternatively spliced-estrogen receptor (ER) mRNA variants has been revealed in the breast cancer tissues. The ER variants transcribed from these mRNA variants were supposed to cause changes in the estrogen responsiveness of breast cancer. Although uterine endometrial cancer also has an estrogen-dependent profile, these ER mRNA variants have not yet been reported in the tumor. In the present study, we attempted to detect the exon 7 deletion-(del.7-) and exon 5 deletion (del.5) ER mRNA variants in normal human uterine endometrium (hEM) and uterine endometrial cancer tissue (hEC) by the use of reverse transcription-polymerase chain reaction-Southern blotting (RT-PCR-SB) with the PCR primers: hE4 (forward), hE6 (reverse), and hE8 (reverse), which were located in exons 4, 6, and 8, respectively. Two major products were generated from RNAs of both hEM and hEC with primers hE4 and hE8. The nucleotide sequence of the longer product was identical to exon 4-8 of human ER cDNA, whereas that of the shorter one completely deleted exon 7. Moreover, when the RT-PCR was done with the primers hE4 and hE6, the shorter product lacking exon 5 was detected with the longer one having the same sequence as exon 4-6 of human ER cDNA. Since the RT-PCR-SB with primers hE4 and hE8 produced a very low or undetectable level of the signals corresponding to del.5 ER mRNA variant, the level of del.7 ER mRNA variant seemed to be higher than that of del.5 ER mRNA variant. These results strongly suggested that both de1.7-and del.5 ER mRNA variants exist in the normal uterine endometrium as well as in endometrial cancer. The ER variants, possibly expressed in these tissues, may play a physiological and/or pathological role.

Recurrent hormone-binding domain truncated ESR1 amplifications in primary endometrial cancers suggest their implication in hormone independent growth

“…The gene truncations we report in endometrial carcinoma disrupt the hormone-binding domain encoding sequence of ESR1 . Similarly, mRNA splice variants lacking one or more of exons 5–8, encoding the hormone-binding domain, have been described in normal 35 36 37 38 and malignant 22 23 35 36 37 39 breast as well as in normal 22 40 41 42 43 44 45 and malignant 42 43 44 45 46 endometrial tissue. Point mutations of the ligand binding domain encoding sequence of ESR1 have also been described to occur in both breast and endometrial cancers 25 26 27 30 47 48 .…”

Analysis of correlation between transcription activity of estrogen-dependent genes of cytochrome P450 and profile of estrogen receptor in endometrial adenocarcinoma

“…It is highly likely that neoplastic tissues change signaling dependent on estrogen receptors. According to Hirat et al, the variants of ER mRNA alternative splicing play a significant role in the oncogenesis of estrogen--dependent tissues [17]. The paper presents the assessment of the ER-alpha and ER-beta gene expressions in the case of endometrial adenocarcinoma as well endometrium without neoplastic changes.…”

“…Higher values of the expression of the ER-alpha/delta2, ER-alpha/delta3 and ER/delta6 isoforms were also observed in cancer tissue, compared to endometrium without neoplastic changes. The ER-alpha/delta5 and ER-alpha/delta6 isoforms, lacking exons coding the LBD fragment, determine the hormone-dependent AF2 transactivation and li-odgrywają warianty alternatywnego składania mRNA ERs [17]. W niniejszej pracy przedstawiono ocenę ekspresji genów ER-alfa i ER-beta w gruczolakoraku endometrium oraz endometrium niezmienionym nowotworowo.…”

Expression of a dominant negative estrogen receptor alpha variant in transgenic mice accelerates uterine cancer induced by the potent estrogen diethylstilbestrol

“…In humans, transcripts for ERΔ3 [63] and other ERα splicing variants [26, 64, 65] have been detected in the normal human endometrium. No difference in ERΔ3 endometrial expression was detected between infertile and fertile women and patients with endometriosis.…”

“…A few studies have also verified that the variant RNA is translated into receptor proteins in human tissues and breast cancer cell lines [21–25]. Although the majority of the reports have focused on ER variant expression in breast cancer, ER variant expression has been found in other normal and neoplastic estrogen target tissues [21], including the uterus [26, 27]. The presence of ER variants in normal tissues suggests that these modified receptors may have a role in normal physiology, estrogen responsiveness, and, perhaps, tumor development.…”