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

Available for download on Thursday, September 09, 2021

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