DOI
https://doi.org/10.25772/P0RD-6881
Author ORCID Identifier
0000-0002-5830-1063
Defense Date
2020
Document Type
Dissertation
Degree Name
Doctor of Philosophy
Department
Human Genetics
First Advisor
Charles V. Clevenger, M.D., Ph.D.
Second Advisor
J. Chuck Harrell, Ph.D.
Third Advisor
Jolene J. Windle, Ph.D.
Fourth Advisor
Paula D. Bos, Ph.D.
Fifth Advisor
Senthil K. Radhakrishnan, Ph.D.
Abstract
The hormone prolactin (PRL) and its receptor (hPRLr) are significantly involved in breast cancer pathogenesis. The intermediate hPRLr (hPRLrI) is an alternatively-spliced isoform, capable of stimulating cellular viability and proliferation. An analogous truncated mouse PRLr (mPRLr) was recently found to be oncogenic when co-expressed with wild-type mPRLr. hPRLrI co-expression with full-length hPRLr (hPRLrL) in MCF10AT cells resulted in robust in vivo and in vitro transformation, while hPRLrI knock-down in MCF7 cells significantly decreased in vitro malignant potential. hPRLrL+I heterodimers displayed greater stability than hPRLrL homodimers, and while being capable of activating Jak2, Ras, and MAPK, they were unable to induce Stat5a tyrosine phosphorylation. Both immunohistochemical breast cancer tissue microarray data and RNA sequencing analyses using The Cancer Genome Atlas (TCGA) identified that higher hPRLrI expression associates with triple-negative breast cancer. These studies indicate the hPRLrI, when expressed alongside hPRLrL, participates in mammary transformation, and represents a novel oncogenic mechanism.
Rights
© The Author
Is Part Of
VCU University Archives
Is Part Of
VCU Theses and Dissertations
Date of Submission
9-9-2020