Elucidating the Role of PTEN and the Focal Adhesion Pathway in Breast Cancer Dormancy Brian Andrew Benz

Format:

Book

Thesis/Dissertation

Author/Creator:

Benz, Brian Andrew, author.

Contributor:

University of Pennsylvania. Cell and Molecular Biology., degree granting institution.

Language:

English

Subjects (All):

0212.

0307.

0379.

0992.

Local Subjects:

0212.

0307.

0379.

0992.

Physical Description:

1 electronic resource (229 pages)

Contained In:

Dissertations Abstracts International 87-07A

Place of Publication:

Ann Arbor : ProQuest Dissertations and Theses, 2025

Language Note:

English

Summary:

Most breast cancer related deaths are the result of metastatic recurrence. The long latencies between initial primary tumor treatment and detection of recurrent disease suggest that surviving residual tumor cells pass through a state of dormancy. The tumor suppressor PTEN is associated with poor prognosis and therapy resistance in breast cancer, but it has not previously been implicated in regulating the dormant state. In this thesis, a CRISPR-Cas9 screen was performed in a doxycycline inducible Her2 (iHer2) model of breast cancer dormancy to evaluate potential regulators of breast cancer dormancy and recurrence and identified PTEN as the top candidate. The aim of this thesis was to investigate the role of PTEN in dormancy and determine its effects on breast cancer recurrence. In the iHer2 model, PTEN loss dramatically accelerated recurrence and tumors failed to completely regress following Her2 downregulation, suggesting abrogation of the latent phase. Furthermore, cells with PTEN loss exhibited a competitive advantage in vivo throughout dormancy and maintained higher rates of proliferation in both a therapy-associated and microenvironmental-induced model of breast cancer dormancy during dormancy at time points at which PTEN wild-type cells remained dormant. Barcoding analysis confirmed that in the PTEN wild type iHer2 model, no clones continuously expanded following Her2 downregulation, and that recurrent tumors arising in the model were monoclonal or oligoclonal, as expected in a model in which recurrences arise from a dormant population of cells. In contrast, barcoding analysis demonstrated that a subpopulation of PTEN-deficient iHer2 clones continuously expanded following Her2 downregulation, suggesting that a subset of cells had failed to enter a dormant state, and resulted in the rapid development of polyclonal recurrent tumors. Strikingly, we found that it was the same population of PTEN-deficient clones that reproducibly continued to expand following Her2 downregulation across different lesions, suggesting that PTEN loss was able to confer the ability to evade entrance into the dormant state on a subset of clones, but not others. In aggregate, our findings support the hypothesis that loss of PTEN accelerates recurrence by preventing residual tumor cells from entering a dormant state and promoting continued proliferation

Notes:

Advisors: Chodosh, Lewis A. Committee members: Brady, Donita C.; Ridky, Todd W.; Drapkin, Ronny; Boerckel, Joel D.

Source: Dissertations Abstracts International, Volume: 87-07, Section: A.

Ph.D. University of Pennsylvania 2025

Vendor supplied data

Local Notes:

School code: 0175

ISBN:

9798276006567

Access Restriction:

Restricted for use by site license