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Increased expression of estrogen-receptor exon-5-deletion variant in relapse tissues of human breast cancer
P Gallacchi1, F Schoumacher, S Eppenberger-Castori
1Department of Research, University Women's Clinic, Basel, Switzerland.
Abstract:
A substantial percentage (30-70%) of human breast carcinomas that initially respond to endocrine therapy acquire resistance during the treatment. Many patients with tumor progression despite treatment with anti-estrogen tamoxifen show continued expression of estrogen receptors (ER) and/or progesterone receptors (PgR) in the relapse tissue. This indicates that, in these tumors, mechanisms other than loss of ER expression are responsible for treatment failure. We have investigated the occurrence and frequency of the exon-5-deletion variant (d5) of ER in human breast-cancer biopsies and in normal tissues. In all normal and tumor tissues tested, both wild-type (wt) and d5 were detected, indicating that expression of the d5 variant is a naturally occurring polymorphism. However, the primary tumors of patients who relapse within 15 months (n = 13) express higher ratios of d5 than do those of patients with no relapse during the same period (p = 0.4, n = 19), though this difference is statistically not significant. A significant increase in the expression level of d5 was determined in relapse as compared with the respective primary tumor (p = 0.02). These data indicate that increased expression of the ER exon-5-deletion variant in relapse tissues might be due to clonal selection of cells resistant to anti-estrogen treatment.
Insights
Endocrine therapy resistance in breast cancer is common. A specific estrogen receptor (ER) variant, d5, significantly increases in expression upon relapse, suggesting it drives resistance to anti-estrogen treatments.
Area of Science:
- Oncology
- Molecular Biology
- Endocrinology
Background:
- Endocrine therapy resistance is a major challenge in breast cancer treatment, affecting 30-70% of patients.
- Tumor progression despite tamoxifen treatment often occurs with continued estrogen receptor (ER) and progesterone receptor (PgR) expression.
- Mechanisms beyond ER loss contribute to treatment failure in endocrine-resistant breast cancers.
Purpose of the Study:
- To investigate the presence and frequency of the ER exon-5-deletion variant (d5) in breast cancer tissues.
- To determine if the d5 variant is associated with endocrine therapy resistance and relapse.
Main Methods:
- Analysis of wild-type (wt) ER and d5 variant expression in normal and tumor breast tissues.
- Comparison of d5 variant ratios in primary tumors of patients with and without early relapse (within 15 months).
- Quantification of d5 variant expression levels in relapse tissue versus corresponding primary tumors.
Main Results:
- The d5 ER variant is a naturally occurring polymorphism found in both normal and tumor tissues.
- Primary tumors from patients who relapsed within 15 months showed a trend towards higher d5 ratios, though not statistically significant.
- A statistically significant increase in d5 variant expression was observed in relapse tissues compared to their respective primary tumors (p=0.02).
Conclusions:
- Increased expression of the ER exon-5-deletion variant in relapse tissues suggests its potential role in acquired resistance to anti-estrogen therapy.
- Clonal selection of cells expressing higher levels of the d5 variant may contribute to treatment failure.
- The d5 variant represents a potential biomarker for predicting or understanding endocrine resistance in breast cancer.