Loss function of tumor suppressor FRMD8 confers resistance to tamoxifen therapy via a dual mechanism
Curation statements for this article:-
Curated by eLife
eLife Assessment
This manuscript presents a valuable finding on the impact of FRMD8 loss on tumor progression and the resistance to tamoxifen therapy. The author conducted systematic experiments to explore the role of FRMD8 in breast cancer and its potential regulatory mechanisms, confirming that FRMD8 affects tamoxifen resistance and convincingly validating this hypothesis through a series of experiments.
This article has been Reviewed by the following groups
Listed in
- Evaluated articles (eLife)
Abstract
Approximately 40% ERα-positive breast cancer patients suffer from therapeutic resistance to tamoxifen. Although reduced ERα level is the major cause of tamoxifen resistance, the underlying mechanisms remain elusive. Here, we report that FRMD8 raises the level of ERα at both transcriptional and post-translational layers. FRMD8 deficiency in MMTV-Cre + ; Frmd8 fl/fl ; PyMT mice accelerates mammary tumor growth and loss of luminal phenotype, and confers tamoxifen resistance. Single-cell RNA profiling reveals that Frmd8 loss decreases the proportion of hormone-sensing differentiated epithelial cells and downregulates the levels of ERα. Mechanically, on one hand, loss of FRMD8 inhibits ESR1 transcription via suppressing the expression of FOXO3A, a transcription factor of ESR1 . On the other hand, FRMD8 interacts both with ERα and UBE3A, and disrupts the interaction of UBE3A with ERα, thereby blocking UBE3A-mediated ERα degradation. In breast cancer patients, FRMD8 gene promoter is found hypermethylated and low level of FRMD8 predicts poor prognosis. Therefore, FRMD8 is an important regulator of ERα and may control therapeutic sensitivity to tamoxifen in ERα-positive breast cancer patients.
Article activity feed
-
eLife Assessment
This manuscript presents a valuable finding on the impact of FRMD8 loss on tumor progression and the resistance to tamoxifen therapy. The author conducted systematic experiments to explore the role of FRMD8 in breast cancer and its potential regulatory mechanisms, confirming that FRMD8 affects tamoxifen resistance and convincingly validating this hypothesis through a series of experiments.
-
Reviewer #1 (Public review):
Summary:
Tamoxifen resistance is a common problem in partially ER-positive patients undergoing endocrine therapy, and this manuscript has important research significance as it is based on clinical practical issues. The manuscript discovered that the absence of FRMD8 in breast epithelial cells can promote the progression of breast cancer, thus proposing the hypothesis that FRMD8 affects tamoxifen resistance and validating this hypothesis through a series of experiments. The manuscript has a certain theoretical reference value.
Strengths:
At present, research on the role of FRMD8 in breast cancer is very limited. This manuscript leverages the MMTV-Cre+;Frmd8fl/fl;PyMT mouse model to study the role of FRMD8 in tamoxifen resistance, and single-cell sequencing technology discovered the interaction between FRMD8 …
Reviewer #1 (Public review):
Summary:
Tamoxifen resistance is a common problem in partially ER-positive patients undergoing endocrine therapy, and this manuscript has important research significance as it is based on clinical practical issues. The manuscript discovered that the absence of FRMD8 in breast epithelial cells can promote the progression of breast cancer, thus proposing the hypothesis that FRMD8 affects tamoxifen resistance and validating this hypothesis through a series of experiments. The manuscript has a certain theoretical reference value.
Strengths:
At present, research on the role of FRMD8 in breast cancer is very limited. This manuscript leverages the MMTV-Cre+;Frmd8fl/fl;PyMT mouse model to study the role of FRMD8 in tamoxifen resistance, and single-cell sequencing technology discovered the interaction between FRMD8 and ESR1. At the mechanistic level, this manuscript has demonstrated two ways in which FRMD8 affects ERα, providing some new insights into the development of ER-positive breast cancer in patients who are resistant to tamoxifen.
Weaknesses:
This manuscript repeatedly emphasizes the role of FRMD8/FOXO3A in tamoxifen resistance in ER-positive breast cancer, but the specific mechanisms have not yet been fully elucidated. Whether FRMD8 can become a biomarker should be verified in large clinical samples or clinical data.
-
Reviewer #2 (Public review):
Summary:
The manuscript presents a valuable finding on the impact of FRMD8 loss on tumor progression and the resistance to tamoxifen therapy. The author conducted systematic experiments to explore the role of FRMD8 in breast cancer and its potential regulatory mechanisms, confirming that FRMD8 could serve as a potential target to revere tamoxifen resistance.
Strengths:
The majority of the research is logically clear, smooth, and persuasive.
Weaknesses:
Some research in the article lacks depth and some sentences are poorly organized.
-
-
-
