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A stemness-related ZEB1-MSRB3 axis governs cellular pliancy and breast cancer genome stability.

Anne-Pierre Morel^1,2, Christophe Ginestier³, Roxane M Pommier^1,2

¹Université de Lyon, Université Claude Bernard Lyon 1, INSERM 1052, CNRS 5286, Centre Léon Bérard, Cancer Research Center of Lyon, Equipe Labellisée Ligue contre le Cancer, Lyon, France.

Nature Medicine

|April 11, 2017

Summary

Tumor development can occur without chromosomal instability (CIN). Mammary stem cells resist oncogene-induced DNA damage via ZEB1 and MSRB3, increasing susceptibility to malignant transformation and potentially driving specific breast cancer subtypes.

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Area of Science:

Oncology
Cell Biology
Genetics

Background:

Chromosomal instability (CIN) is a key driver of tumorigenesis in most neoplasms.
Some cancers, like certain triple-negative breast cancers, develop with minimal genomic aberrations, suggesting alternative oncogenic pathways.
The differentiation status of normal human mammary epithelial cells influences their response to oncogenic events.

Purpose of the Study:

To investigate how mammary epithelial cell differentiation affects genetic routes toward malignancy.
To identify mechanisms by which tumor development can occur in the absence of CIN.
To explore the role of ZEB1 and MSRB3 in oncogene-induced DNA damage resistance in mammary stem cells.

Main Methods:

Induction of oncogenes in differentiated versus stem mammary epithelial cells.
Analysis of DNA damage response pathways, including p53-dependent pathways.
Assessment of ZEB1 and MSRB3 expression and function.
Pathological and genomic analysis of breast neoplasms.

Main Results:

Differentiated mammary cells exhibit massive DNA damage upon oncogene induction.
Mammary stem cells are resistant to oncogene-induced DNA damage due to a ZEB1 and MSRB3 driven program.
This resistance prevents p53-dependent DNA damage response, enhancing malignant transformation susceptibility in stem cells.
A subset of breast neoplasms shows high ZEB1, low TP53 mutation frequency, and low CIN, aligning with the proposed model.

Conclusions:

Mammary stem cell differentiation status dictates oncogenic response and malignancy pathways.
ZEB1 and MSRB3 play a crucial role in protecting stem cells from DNA damage, facilitating transformation without CIN.
This mechanism explains a subclass of breast cancers characterized by low CIN and high ZEB1.