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Investigation Of The Role Of Mkk7 In Multi-drug Resistant Er+ Breast Cancer

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Estrogen receptor-positive (ER+) breast cancer accounts for 67-80% of all breast cancer subtypes. Endocrine therapies are initially given as part of first-line treatment, however 20% of the patients develop resistance. The overactivation of cyclin dependent kinase 4/6 (CDK4/6) is one of the underlying mechanisms. Hence the addition of CDK4/6 inhibitors such as palbociclib in combination with endocrine therapy has emerged as the new standard-of-care for advanced or metastatic ER+ breast cancer. While this treatment works in the short-term, unfortunately resistance towards endocrine therapy and CDK4/6 inhibitors is still inevitable. CRISPR/Cas9 screens from the Caldon lab found that MKK7 from the JNK pathway is lost in therapy resistance. Moreover, patients with low MKK7 respond poorly to treatments. Hence, to validate the role of MKK7 loss in inducing drug resistance, gene and protein expressions of JNK target genes, which are the AP-1 transcription factors (Jun, Fos families, and ATF3), were analyzed using quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) and western blot. Furthermore, to determine the ability of tumor progression under treatments, evaluating the drug tolerability in vivo is essential. The findings suggest that c-Jun (JUN) was downregulated in MKK7 knockout MCF-7 and T-47D cells, Fos was not disrupted, and ATF3 protein was downregulated in MKK7 knockout T-47D cells. Endocrine therapy and CDK4/6 inhibition treatment was also found to be well-tolerated in mice.

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Detail Information

Series Title

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Call Number

EP BM-012

Publisher

i3L, Jakarta : i3L, Jakarta., 2024

Collation

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Language

English

ISBN/ISSN

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Classification

EP BM-012

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Edition

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Subject(s)

ER+ breast cancer
JNK signaling
MKK7
endocrine therapy and CDK4/6 inhibitor resistance
AP-1 transcription factors

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