Multiple splicing variants of the estrogen receptor are present in individual human breast tumors.
Transcript variants of the estrogen receptor (ER) were investigated in 109 primary breast tumors using reverse transcription-polymerase chain reaction (RT-PCR) and primers allowing analysis of each internal exon. A high incidence of different ER variants was observed, each individual tumor often manifesting multiple variants coexisting with corresponding wildtype (wt) ER. These variants, by sequence analysis confirmed to represent exon splicing deletions, included ER deltaE2 (found in 41% of the tumors examined), ER deltaE3 (74%), ER deltaE4 (72%), ER deltaE5 (66%), and ER deltaE7 (88%). No evidence of transcripts lacking exon 6 was found, although a ER deltaE5,7 variant manifesting simultaneous deletion of exons 5 and 7 was observed. The presence of specific ER variants was not significantly correlated to the status of ER and progesterone receptor (PgR) protein expression, as assessed by routine analysis, although a trend towards a higher incidence of ER deltaE3 and increased expression of ER deltaE7 in ER+/PgR- tumors was observed, suggesting a dominant inhibitory effect on normal ER function to be involved. Moreover, ER deltaE4 was more common in ER+ tumors, possibly due to a cytoplasmic sequestring of this variant lacking a nuclear localization sequence. The presence of ER variants was not associated to clinicopathological variables, and equally frequent in tumors from patients having recurred or remained recurrence-free during adjuvant tamoxifen therapy. In conclusion, although ER splicing variants are abundant in breast cancer, the present study provides no evidence for a direct role of these ER variants in tumor development and tamoxifen resistance. It remains possible, however, that minor cell clones within the tumor, undetected by analysis of tumor homogenates, displaying extreme difference in content of ER variants, could be selected for during therapy or metastasis.
Zhang
Q X
QX
Department of Oncology, University Hospital, Lund, Sweden.
Hilsenbeck
S G
SG
Fuqua
S A
SA
Borg
A
A
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D017398:Alternative Splicing; D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy / Q000235:genetics*; D018572:Disease-Free Survival; D019008:Drug Resistance, Neoplasm; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D012334:RNA, Neoplasm / Q000032:analysis / Q000235:genetics*; D011960:Receptors, Estrogen / Q000032:analysis / Q000235:genetics*; D011980:Receptors, Progesterone / Q000032:analysis / Q000235:genetics; D012008:Recurrence; D013629:Tamoxifen / Q000627:therapeutic use
D018931:Antineoplastic Agents, Hormonal; D012333:RNA, Messenger; D012334:RNA, Neoplasm; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D013629:Tamoxifen