TY - JOUR
T1 - Identification of a Notch transcriptomic signature for breast cancer
AU - Braune, Eike Benjamin
AU - Geist, Felix
AU - Tang, Xiaojia
AU - Kalari, Krishna
AU - Boughey, Judy
AU - Wang, Liewei
AU - Leon-Ferre, Roberto A.
AU - D’Assoro, Antonino B.
AU - Ingle, James N.
AU - Goetz, Matthew P.
AU - Kreis, Julian
AU - Wang, Kang
AU - Foukakis, Theodoros
AU - Seshire, Anita
AU - Wienke, Dirk
AU - Lendahl, Urban
N1 - Publisher Copyright:
© 2024, The Author(s).
PY - 2024/12
Y1 - 2024/12
N2 - Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier. Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets. Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions: The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.
AB - Background: Dysregulated Notch signalling contributes to breast cancer development and progression, but validated tools to measure the level of Notch signalling in breast cancer subtypes and in response to systemic therapy are largely lacking. A transcriptomic signature of Notch signalling would be warranted, for example to monitor the effects of future Notch-targeting therapies and to learn whether altered Notch signalling is an off-target effect of current breast cancer therapies. In this report, we have established such a classifier. Methods: To generate the signature, we first identified Notch-regulated genes from six basal-like breast cancer cell lines subjected to elevated or reduced Notch signalling by culturing on immobilized Notch ligand Jagged1 or blockade of Notch by γ-secretase inhibitors, respectively. From this cadre of Notch-regulated genes, we developed candidate transcriptomic signatures that were trained on a breast cancer patient dataset (the TCGA-BRCA cohort) and a broader breast cancer cell line cohort and sought to validate in independent datasets. Results: An optimal 20-gene transcriptomic signature was selected. We validated the signature on two independent patient datasets (METABRIC and Oslo2), and it showed an improved coherence score and tumour specificity compared with previously published signatures. Furthermore, the signature score was particularly high for basal-like breast cancer, indicating an enhanced level of Notch signalling in this subtype. The signature score was increased after neoadjuvant treatment in the PROMIX and BEAUTY patient cohorts, and a lower signature score generally correlated with better clinical outcome. Conclusions: The 20-gene transcriptional signature will be a valuable tool to evaluate the response of future Notch-targeting therapies for breast cancer, to learn about potential effects on Notch signalling from conventional breast cancer therapies and to better stratify patients for therapy considerations.
KW - Basal-like
KW - Breast cancer
KW - Breast cancer stem cell
KW - Diagnostics
KW - Notch signalling
KW - Therapy
KW - Therapy resistance
KW - Transcriptomic signature
KW - Triple-negative
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U2 - 10.1186/s13058-023-01757-7
DO - 10.1186/s13058-023-01757-7
M3 - Article
C2 - 38172915
AN - SCOPUS:85181250554
SN - 1465-5411
VL - 26
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 4
ER -