Cooperative Genomic Events Driving Mutant TP53-Driven DCIS Progression

Author

Rhiannon L. Morrissey, The University of Texas MD Anderson Cancer CenterFollow

Author ORCID Identifier

0000-0001-9160-1722

Date of Graduation

12-2025

Document Type

Dissertation (PhD)

Program Affiliation

Genetics and Epigenetics

Degree Name

Doctor of Philosophy (PhD)

Advisor/Committee Chair

Guillermina Lozano, Ph.D.

Committee Member

Alastair Thompson, M.D.

Committee Member

Nicholas Navin, Ph.D.

Committee Member

Florencia McAllister, M.D.

Committee Member

Jeffrey Frost, Ph.D.

Committee Member

Adel El-Naggar, M.D.

Abstract

Ductal carcinoma in situ (DCIS) is a mammary lesion characterized by abnormal epithelial cells occurring in mammary ducts while still being confined to the luminal space. Not all DCIS becomes invasive, and no strategy currently exists in patients to stratify indolent DCIS from DCIS at risk of progression. The standard of care includes surgical resection and radiation therapy, which constitutes overtreatment for most women whose DCIS would not progress forward. Several studies of human DCIS and breast cancer suggest that TP53 mutations occur early in DCIS, suggesting a critical role for mutant TP53 in driving disease progression. Using a somatic mouse model of p53^R245W induced breast cancer (equivalent to the TP53^R248W hotspot mutation in humans), we identified DCIS lesions. Through exome-sequencing and low pass whole-genome sequencing, we identified genomic changes shared between DCIS and invasive tumors. This comparison nominated seven murine candidate genes, with eight human orthologs. We assessed the cooperativity of these genes with mutant TP53 in human MCF-10A cells using acinar morphogenesis and migration assays. Overexpression of TMEM267 in cells with mutant TP53 caused a significant increase in the filled duct, DCIS-like phenotype. RNAscope revealed increased expression of Tmem267 in DCIS as compared to normal ducts, and a statistically significant increase in Tmem267 expression in mammary tumors. We nominate TMEM267 as a cooperating event with mutant TP53 in DCIS progression.

Recommended Citation

Morrissey, Rhiannon L., "Cooperative Genomic Events Driving Mutant TP53-Driven DCIS Progression" (2025). Dissertations & Theses (Open Access). 1486.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1486

Keywords

Breast Cancer, Ductal carcinoma in situ, DCIS, Mutant TP53, TMEM267, Mouse Models