ACK1 is dispensable for development, skin tumor formation, and breast cancer cell proliferation

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Activated Cdc42-associated kinase 1 (ACK1) is a nonreceptor tyrosine kinase frequently amplified in cancers.
• ACK1 interacts with key cancer-related molecules like Cdc42 and EGFR, suggesting a role in tumorigenesis.
• Its precise function in normal development and cancer progression remains unclear.

Purpose of the Study:

• To investigate the role of ACK1 in mammalian development and tumor formation.
• To determine ACK1's involvement in EGFR and Cdc42 signaling pathways.
• To assess the impact of ACK1 deletion on cancer cell growth and migration.

Main Methods:

• Generated ACK1 knockout (ACK1 ko) mice using CRISPR genome editing.
• Analyzed development, fertility, and tissue maintenance in ACK1 ko mice.
• Assessed EGFR, Akt, and Erk phosphorylation in primary ACK1-null keratinocytes and breast cancer cell lines (MDA-MB-231, 67NR, MCF7, 4T1, T47D).
• Evaluated DMBA/TPA-induced skin tumor formation and EGF-induced signaling.
• Studied the effect of ACK1 loss on cell migration in MDA-MB-231 and T47D cells.

Main Results:

• ACK1 ko mice exhibited normal development, fertility, and tissue maintenance.
• ACK1-null keratinocytes showed normal EGFR phosphorylation but a trend towards reduced Akt and Erk activation.
• No significant differences in DMBA/TPA-induced skin tumor formation were observed between ACK1 ko and control mice.
• ACK1 deletion did not affect the growth of various breast cancer cell lines.
• EGF-induced Erk, Akt, and p130Cas phosphorylation, as well as directed cell migration, were largely unaffected by ACK1 loss.

Conclusions:

• The study does not support a major role for ACK1 in Cdc42 and EGFR signaling.
• ACK1 appears dispensable for normal mammalian development and tumor formation.
• These findings challenge the proposed significance of ACK1 in cancer progression.