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PCSK5M452I Is a Recessive Hypomorph Exclusive to MCF10DCIS.com Cells.

Taylor Marohl¹, Kristen A Atkins², Lixin Wang¹

¹Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia.

Molecular Cancer Research : MCR

|October 28, 2025

Summary

This summary is machine-generated.

A rare proprotein convertase subtilisin/kexin type 5 (PCSK5) mutation in the MCF10DCIS.com cell line does not cause its unique premalignant properties. This finding reassures researchers using this common breast cancer model.

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Area of Science:

Biochemistry
Cell Biology
Cancer Research

Background:

The MCF10DCIS.com cell line is a key model for studying ductal carcinoma in situ (DCIS) premalignancy.
This cell line harbors a unique heterozygous M452I mutation in proprotein convertase subtilisin/kexin type 5 (PCSK5), an enzyme crucial for maturing growth differentiation factor 11 (GDF11).
GDF11 is known to suppress triple-negative breast cancer progression, making the PCSK5 mutation's role in MCF10DCIS.com properties a relevant question.

Purpose of the Study:

To investigate whether the PCSK5M452I mutation contributes to the distinct characteristics of the MCF10DCIS.com cell line.
To assess the activity and cellular behavior of the PCSK5M452I mutant enzyme.
To determine if the PCSK5M452I mutation confers gain-of-function or loss-of-function properties relevant to DCIS progression.

Main Methods:

Utilized an optimized in-cell GDF11 maturation assay to measure PCSK5M452I activity.
Generated a PCSK5 knockout (PCSK5-/-) MCF10DCIS.com clone and reconstituted it with different PCSK5 alleles (wildtype, M452I, T288P null).
Assessed cellular organization in 3D matrigel cultures and growth of intraductal xenografts for different PCSK5 genotypes.

Main Results:

Overexpressed PCSK5M452I showed measurable but reduced activity compared to wildtype PCSK5.
PCSK5M452I exhibited mild defects in anterograde transport.
Cells with PCSK5M452I displayed disorganized multicellular structures in 3D cultures and impaired xenograft growth, similar to PCSK5 null cells, indicating a hypomorphic (loss-of-function) phenotype.

Conclusions:

The PCSK5M452I mutation is hypomorphic, meaning it has reduced but not absent function.
The remaining wildtype PCSK5 allele in MCF10DCIS.com compensates for the hypomorphic M452I mutation.
This study reassures that the unusual PCSK5 mutation is not the cause of the MCF10DCIS.com cell line's characteristic premalignant properties.