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SMAD4 depletion contributes to endocrine resistance by integrating ER and ERBB signaling in HR + HER2- breast cancer.
- Source :
-
Cell death & disease [Cell Death Dis] 2024 Jun 24; Vol. 15 (6), pp. 444. Date of Electronic Publication: 2024 Jun 24. - Publication Year :
- 2024
-
Abstract
- Endocrine resistance poses a significant clinical challenge for patients with hormone receptor-positive and human epithelial growth factor receptor 2-negative (HR + HER2-) breast cancer. Dysregulation of estrogen receptor (ER) and ERBB signaling pathways is implicated in resistance development; however, the integration of these pathways remains unclear. While SMAD4 is known to play diverse roles in tumorigenesis, its involvement in endocrine resistance is poorly understood. Here, we investigate the role of SMAD4 in acquired endocrine resistance in HR + HER2- breast cancer. Genome-wide CRISPR screening identifies SMAD4 as a regulator of 4-hydroxytamoxifen (OHT) sensitivity in T47D cells. Clinical data analysis reveals downregulated SMAD4 expression in breast cancer tissues, correlating with poor prognosis. Following endocrine therapy, SMAD4 expression is further suppressed. Functional studies demonstrate that SMAD4 depletion induces endocrine resistance in vitro and in vivo by enhancing ER and ERBB signaling. Concomitant inhibition of ER and ERBB signaling leads to aberrant autophagy activation. Simultaneous inhibition of ER, ERBB, and autophagy pathways synergistically impacts SMAD4-depleted cells. Our findings unveil a mechanism whereby endocrine therapy-induced SMAD4 downregulation drives acquired resistance by integrating ER and ERBB signaling and suggest a rational treatment strategy for endocrine-resistant HR + HER2- breast cancer patients.<br /> (© 2024. The Author(s).)
- Subjects :
- Humans
Female
Cell Line, Tumor
Animals
Tamoxifen pharmacology
Tamoxifen therapeutic use
Tamoxifen analogs & derivatives
Mice
Antineoplastic Agents, Hormonal pharmacology
Antineoplastic Agents, Hormonal therapeutic use
Mice, Nude
Gene Expression Regulation, Neoplastic drug effects
Autophagy drug effects
ErbB Receptors metabolism
ErbB Receptors genetics
Smad4 Protein metabolism
Smad4 Protein genetics
Breast Neoplasms metabolism
Breast Neoplasms genetics
Breast Neoplasms pathology
Breast Neoplasms drug therapy
Signal Transduction drug effects
Drug Resistance, Neoplasm drug effects
Drug Resistance, Neoplasm genetics
Receptor, ErbB-2 metabolism
Receptor, ErbB-2 genetics
Receptors, Estrogen metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 2041-4889
- Volume :
- 15
- Issue :
- 6
- Database :
- MEDLINE
- Journal :
- Cell death & disease
- Publication Type :
- Academic Journal
- Accession number :
- 38914552
- Full Text :
- https://doi.org/10.1038/s41419-024-06838-9