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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, VA 22908.
Biorxiv : the Preprint Server for Biology
|March 17, 2025
Summary
A rare proprotein convertase PCSK5 mutation (M452I) in the MCF10DCIS.com cell line does not cause its unique properties. This breast cancer model
Area of Science:
- * Molecular biology
- * Cancer research
- * Cell biology
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), a gene not previously linked to human cancers.
- * PCSK5 is known to process growth differentiation factor 11 (GDF11), a ligand that inhibits triple-negative breast cancer progression.
Purpose of the Study:
- * To investigate whether the PCSK5M452I mutation contributes to the distinct characteristics of the MCF10DCIS.com cell line.
- * To determine the functional impact of the PCSK5M452I mutation on GDF11 maturation and cellular behavior.
- * To assess the mutation's role in breast cancer premalignancy models.
Main Methods:
- * Utilized an optimized in-cell assay to measure GDF11 maturation by PCSK5 variants.
- * Created a PCSK5 knockout MCF10DCIS.com clone and reconstituted it with wildtype PCSK5, PCSK5M452I, and PCSK5T288P (null) alleles.
- * Evaluated cellular organization in 3D matrigel cultures and growth of intraductal xenografts.
- * Assessed parameters including multicellular organization, comedo necrosis, and stromal activation.
Main Results:
- * Overexpressed PCSK5M452I showed measurable but reduced activity compared to wildtype PCSK5.
- * PCSK5M452I exhibited mild defects in anterograde transport.
- * In 3D cultures and xenografts, PCSK5M452I addback cells displayed impaired multicellular organization, reduced growth, and altered tumor microenvironment characteristics, similar to PCSK5 null cells.
- * No gain-of-function activity was observed for PCSK5M452I.
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 mutation.
- * The unique properties of the MCF10DCIS.com cell line are not attributable to the exotic PCSK5M452I mutation.
