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Modeling Heterogeneity of Triple‐Negative Breast Cancer Uncovers a Novel Combinatorial Treatment Overcoming Primary Drug Resistance
- Source :
- Advanced Science, Advanced Science, 2020, pp.2003049. ⟨10.1002/advs.202003049⟩, Advanced Science, 2021, 8 (3), pp.2003049. ⟨10.1002/advs.202003049⟩, Advanced Science, Vol 8, Iss 3, Pp n/a-n/a (2021), Advanced Science, Wiley Open Access, 2020, pp.2003049. ⟨10.1002/advs.202003049⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- Triple‐negative breast cancer (TNBC) is a highly aggressive breast cancer subtype characterized by a remarkable molecular heterogeneity. Currently, there are no effective druggable targets and advanced preclinical models of the human disease. Here, a unique mouse model (MMTV‐R26Met mice) of mammary tumors driven by a subtle increase in the expression of the wild‐type MET receptor is generated. MMTV‐R26Met mice develop spontaneous, exclusive TNBC tumors, recapitulating primary resistance to treatment of patients. Proteomic profiling of MMTV‐R26Met tumors and machine learning approach show that the model faithfully recapitulates intertumoral heterogeneity of human TNBC. Further signaling network analysis highlights potential druggable targets, of which cotargeting of WEE1 and BCL‐XL synergistically kills TNBC cells and efficiently induces tumor regression. Mechanistically, BCL‐XL inhibition exacerbates the dependency of TNBC cells on WEE1 function, leading to Histone H3 and phosphoS33RPA32 upregulation, RRM2 downregulation, cell cycle perturbation, mitotic catastrophe, and apoptosis. This study introduces a unique, powerful mouse model for studying TNBC formation and evolution, its heterogeneity, and for identifying efficient therapeutic targets.<br />Triple‐negative breast cancer (TNBC) is highly aggressive and currently lacks effective treatment. This study reports the generation of a unique mouse model developing spontaneous, exclusive TNBC, recapitulating heterogeneity and primary resistance to treatments. Its clinical relevance is further strengthened by the identification of a potent drug combination for TNBC treatment, based on WEE1 and BCL‐XL targeting.
- Subjects :
- BCL‐XL
General Chemical Engineering
[SDV]Life Sciences [q-bio]
Druggability
General Physics and Astronomy
Medicine (miscellaneous)
Bcl-xL
[SDV.CAN]Life Sciences [q-bio]/Cancer
02 engineering and technology
010402 general chemistry
01 natural sciences
Biochemistry, Genetics and Molecular Biology (miscellaneous)
03 medical and health sciences
Histone H3
0302 clinical medicine
Breast cancer
[SDV.CAN] Life Sciences [q-bio]/Cancer
Downregulation and upregulation
medicine
General Materials Science
WEE1
lcsh:Science
Mitotic catastrophe
Triple-negative breast cancer
030304 developmental biology
0303 health sciences
drug resistance
Full Paper
biology
General Engineering
Full Papers
021001 nanoscience & nanotechnology
medicine.disease
0104 chemical sciences
3. Good health
[SDV] Life Sciences [q-bio]
Wee1
signaling reprogramming
triple‐negative breast cancer
Apoptosis
030220 oncology & carcinogenesis
cancer mouse model
biology.protein
Cancer research
MET
lcsh:Q
0210 nano-technology
Subjects
Details
- Language :
- English
- ISSN :
- 21983844
- Database :
- OpenAIRE
- Journal :
- Advanced Science, Advanced Science, 2020, pp.2003049. ⟨10.1002/advs.202003049⟩, Advanced Science, 2021, 8 (3), pp.2003049. ⟨10.1002/advs.202003049⟩, Advanced Science, Vol 8, Iss 3, Pp n/a-n/a (2021), Advanced Science, Wiley Open Access, 2020, pp.2003049. ⟨10.1002/advs.202003049⟩
- Accession number :
- edsair.doi.dedup.....4a4928f8e7a9413913a642e3fddc91ba