Modeling Neoadjuvant chemotherapy resistance in vitro increased NRP-1 and HER2 expression and converted MCF7 breast cancer subtype.
ATP Binding Cassette Transporter, Subfamily G, Member 2
Antineoplastic Combined Chemotherapy Protocols
Breast Neoplasms
/ drug therapy
Female
Humans
MCF-7 Cells
Neoadjuvant Therapy
Neoplasm Proteins
/ metabolism
Neuropilin-1
/ therapeutic use
Phosphatidylinositol 3-Kinases
Receptor, ErbB-2
/ metabolism
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
05 2020
05 2020
Historique:
received:
14
04
2019
revised:
05
11
2019
accepted:
19
11
2019
pubmed:
29
12
2019
medline:
22
6
2021
entrez:
29
12
2019
Statut:
ppublish
Résumé
Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes. We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC). Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κB The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.
Sections du résumé
BACKGROUND AND PURPOSE
Patients with locally advanced breast cancer usually receive third-generation neoadjuvant chemotherapy (NAC). Although NAC treatment improved the overall survival, patients' response varies, some acquire resistance and others exhibit a conversion in their breast cancer molecular subtype. We aimed to identify the molecular changes involved in NAC resistance attempting to find new therapeutic targets in different breast cancer subtypes.
EXPERIMENTAL APPROACH
We modelled NAC treatments used in clinical practice and generated resistant cell lines in vitro. The resistant cells were generated by consecutive treatment with four cycles of doxorubicin (adriamycin)/cyclophosphamide (4xAC) followed by an additional four cycles of paclitaxel (4xAC + 4xPAC).
KEY RESULTS
Our data revealed distinct mechanisms of resistance depending on breast cancer subtype and drugs used. MDA-MB-231 cells resistant to 4xAC + 4xPAC activated neuropilin-1/TNC/integrin β3/FAK/NF-κB
CONCLUSIONS AND IMPLICATIONS
The concurrent increase in neuropilin-1 and HER2 upon resistance and the inverse relationship between neuropilin-1 and BCRP/ABCG2 suggest that, in addition to HER2, neuropilin-1 status should be assessed in patients undergoing NAC, and as a potential drug target for refractory breast cancer.
Identifiants
pubmed: 31883395
doi: 10.1111/bph.14966
pmc: PMC7161552
doi:
Substances chimiques
ATP Binding Cassette Transporter, Subfamily G, Member 2
0
Neoplasm Proteins
0
Neuropilin-1
144713-63-3
Receptor, ErbB-2
EC 2.7.10.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2024-2041Subventions
Organisme : Sultan Qaboos University
ID : IG/SCI/BIOL/18/03
Pays : International
Organisme : The Research Council of Oman
ID : ORG/HSS/14/006 (TRC#137) SQU# RC/SCI/BIOL/15/02
Pays : International
Informations de copyright
© 2019 The British Pharmacological Society.
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