University of Texas Health Science Center at Houston
Cooperative Genomic Events Driving Mutant TP53-Driven DCIS Progression
Abstract
dc:description.abstract<p>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 <em>TP53</em> mutations occur early in DCIS, suggesting a critical role for mutant <em>TP53</em> in driving disease progression. Using a somatic mouse model of <em>p53<sup>R245W</sup></em> induced breast cancer (equivalent to the <em>TP53<sup>R248W</sup></em> 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 <em>TP53</em> in human MCF-10A cells using acinar morphogenesis and migration assays. Overexpression of <em>TMEM267</em> in cells with mutant <em>TP53</em> caused a significant increase in the filled duct, DCIS-like phenotype. RNAscope revealed increased expression of <em>Tmem267 </em>in DCIS as compared to normal ducts, and a statistically significant increase in <em>Tmem267 </em>expression in mammary tumors. We nominate <em>TMEM267</em> as a cooperating event with mutant <em>TP53</em> in DCIS progression.</p>
Degree
thesis:*- Name thesis:degree_name
- Doctor of Philosophy (PhD)
- Level thesis:degree_level
- Dissertation (PhD)
- Year dc:date.available
- 2025
Author and committee
dc:creator, dc:contributor.*- Authors dc:creator
-
- Morrissey, Rhiannon L
- <h2>0000-0001-9160-1722</h2>
- Contributors dc:contributor
-
- Guillermina Lozano, Ph.D.
- Alastair Thompson, M.D.
- Nicholas Navin, Ph.D.
Subjects
dc:subject × 7Identifiers
dc:identifier.*- Repository record dc:identifier
- https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1486
- OAI identifier oai:identifier
- oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-2543