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Estrogen receptor variants in clinical breast cancer
W L McGuire1, G C Chamness, S A Fuqua
1Division of Medical Oncology, University of Texas Health Science Center, San Antonio 78284-7884.
Abstract:
We have used the screening techniques of chemical mismatch cleavage, single stranded conformational polymorphism, and gel retardation to discover a number of estrogen receptor RNA variants in clinical breast cancer tissues. We have found basepair insertions, transitions, and deletions as well as alternative splicing, yielding deletions of exon 3, 5, or 7. Using a yeast transactivation assay we have discovered receptors with outlaw function, including both a dominant-positive receptor, which is transcriptionally active in the absence of estrogen, and a dominant-negative receptor, which is itself transcriptionally inactive, but prevents the action of normal estrogen receptor. These variants could have clinical significance, helping to explain breast tumor behavior and patient outcome.
Insights
Researchers identified novel estrogen receptor (ER) RNA variants in breast cancer tissues, including those with altered function. These variants may explain tumor behavior and patient outcomes.
Area of Science:
- Molecular Biology
- Cancer Research
- Genetics
Background:
- Estrogen receptor (ER) plays a critical role in breast cancer development and progression.
- Aberrant ER signaling is a hallmark of many breast tumors, influencing treatment response and patient prognosis.
- Understanding ER heterogeneity is crucial for developing targeted therapies.
Purpose of the Study:
- To identify and characterize novel estrogen receptor RNA variants in clinical breast cancer tissues.
- To investigate the functional consequences of these ER variants using transactivation assays.
- To explore the potential clinical significance of ER variants in breast tumor behavior and patient outcomes.
Main Methods:
- Screening techniques including chemical mismatch cleavage, single-stranded conformational polymorphism (SSCP), and gel retardation assays were employed.
- Yeast transactivation assays were utilized to assess the functional activity of identified ER variants.
- Analysis of RNA from clinical breast cancer tissues was performed.
Main Results:
- Multiple estrogen receptor RNA variants were discovered in breast cancer tissues.
- These variants exhibit diverse molecular alterations, including base pair insertions, transitions, deletions, and alternative splicing (e.g., exon 3, 5, or 7 deletions).
- Functional characterization revealed 'outlaw' receptors with dominant-positive (constitutively active) and dominant-negative (inhibitory) functions.
Conclusions:
- Novel estrogen receptor RNA variants with altered functions exist in clinical breast cancer.
- These variants, including dominant-positive and dominant-negative forms, may contribute to aberrant ER signaling.
- The identified ER variants hold potential clinical significance for understanding breast tumor behavior and predicting patient outcomes.