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The Role of Prolactin Receptor Signaling in the Development of Mammary Adenocarcinoma
Date of Award
Doctor of Philosophy (PhD)
Signaling through the prolactin receptor (PrlR) has been associated with human ERa+ breast cancer through several correlative studies. Work in murine models of breast cancer have corroborated these findings by showing that increased PrlR signaling in the mammary gland is to be capable of inducing the development of mammary adenocarcinomas. These results have prompted extensive work on the development of PrlR antagonists that may eventually provide an additional therapeutic modality in the treatment of ERa+ breast cancer. However, a complete understanding of the natural regulation of PrlR-signaling that prevents it from developing into an oncogenic signaling cascade has been lacking. Furthermore, no mouse models of breast cancer have demonstrated, as yet, that a lack of normal PrlR regulation contributes to the outgrowth of mammary adenocarcinomas. Careful studies of such regulation may provide an additional therapeutic target for blocking a potentially oncogenic signaling cascade.
Previous work in our laboratory identified that mice lacking STAT1 develop mammary adenocarcinomas while none of the other immunocompromised mouse strains do. These tumors recapitulate several key features of human luminal breast cancer, including ERa expression and growth-dependence on ovarian hormones. These studies prompted a careful investigation of STAT1 expression in human luminal breast cancer. Immunohistological analyses of human breast cancer revealed that, in fact, a substantial portion (~40%) of human luminal breast cancer exhibits a reduced level of STAT1.
We now show that mammary adenocarcinoma cells of STAT1-/- mice display persistent PrlR signaling, resulting in activation of Janus Kinase-2 (JAK2), STAT3, and STATs 5A/5B, and that these ERa+ mammary tumor cells are addicted to PrlR-JAK2-STAT3/STAT5A/5B signaling. Furthermore, these tumors exhibit increased expression of JAK2 is the result of increased JAK2 transcription.
The pro-oncogenic PrlR signaling in STAT1-/- mammary epithelial cells results from failed upregulation of SOCS1, a STAT1-induced inhibitor of JAK2. Enforced expression of SOCS1 in the STAT1-/- mammary tumors results in decreased PrlR-signaling and cell death. Importantly, blocking the upregulation of SOCS1 using SOCS1-specific shRNA inhibits this cell death. Thus, STAT1 functions as a tumor suppressor in mammary glands by preventing the natural developmental function of a growth factor receptor from becoming pro-oncogenic.
Chair and Committee
Robert D Schreiber
Paul Allen, Marco Colonna, Kenneth M Murphy, Andrey Shaw, Sheila Stewart, Wojciech Swat
Rickert, Charles Gerard, "The Role of Prolactin Receptor Signaling in the Development of Mammary Adenocarcinoma" (2014). Arts & Sciences Electronic Theses and Dissertations. 65.