Thesis

Investigating The Role Of JNK In Multi-drug Resistant ER+ Breast Cancer

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Endocrine therapy and CDK4/6 inhibition are the standard-of-care treatments for patients with
advanced or metastatic estrogen receptor-positive (ER+) breast cancer. Despite improvements in the
overall progression-free survival, resistance develops in patients by unidentified mechanisms.
Preliminary CRISPR/Cas9 screens from the Caldon lab revealed that loss of the MAPK9 gene (encoding
JNK2) led to endocrine therapy and CDK4/6 inhibitor combination resistance. Moreover, loss of JNK
phosphorylation in patients is associated with poorer survival. Here, we validated whether JNK2 or its
paralog, JNK1, promotes combination therapy resistance. Using JNK1 and JNK2 knockout cell lines
generated by the lab, we tested the activation of JNK by short-term anisomycin treatment. We also
tested the activation of senescence and downstream AP-1 transcription factor targets following
treatment with endocrine therapy and CDK4/6 inhibition. Validations were done through qRT-PCR,
western blot, and β-galactosidase assay. Our results revealed that thorough protein suppression was
observed in the respective JNK knockout cell lines, and JNK activation response was diminished in both

JNK knockouts, with prominent results in JNK2-/- cells. The proportion of senescence-associated β-
galactosidase (SA-βgal) positive cells was also decreased in JNK2-/- cells. Phosphorylation of the AP-1

transcription factor c-Jun was downregulated in JNK2-/- cells under basal conditions. To conclude, we
confirmed that JNK2 loss results in changes to JNK activation, as well as a diminished senescence
response to endocrine therapy and CDK4/6 inhibition in MCF-7 cells. This data provides pre-clinical
rationale to screen genetic profile patients before receiving endocrine therapy and CDK4/6 inhibition.

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Detail Information

Series Title

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Call Number

BM 24-040

Publisher

i3L, Jakarta : i3L Press., 2024

Collation

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Language

English

ISBN/ISSN

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Classification

NONE

Content Type

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Media Type

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Carrier Type

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Edition

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Subject(s)

ER+ breast cancer
endocrine therapy
CDK4/6 inhibitors
JNK pathway

Specific Detail Info

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Statement of Responsibility

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