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Access Type

WSU Access

Date of Award

January 2025

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Cancer Biology

First Advisor

Kay-Uwe Wagner

Abstract

Janus kinases (JAK) and Signal Transducers and Activators of Transcription (STATs) constitute a central signaling module relaying hormone and cytokine cues and instructing a multitude of pro-tumorigenic processes such as proliferation, differentiation, and invasion in breast cancers. Previous studies have demonstrated that JAK1 and JAK2 have discrete biological functions in pregnancy-associated mammary gland development and breast tumorigenesis, mediated by specific STAT transcription factors, in particular STAT3, STAT5a, and STAT5b. However, the cooperative and compensatory actions of JAKs and STATs and their effects on early mammary gland development and breast cancer initiation and progression remain largely unknown. Herein, we report that female mice with a mammary epithelial-specific deletion of both JAK1 and JAK2 exhibit a severe block of the development of mammary gland ducts that persists through adulthood. Mammary transplantation experiments confirmed that the essential functions of JAK1 and JAK2 in ductal elongation are mammary-epithelial cell intrinsic. A comparative analysis of mice with combinatorial deletions of Jak1 and Jak2 alleles suggests that JAK2 is the main Janus kinase regulating early mammary ductal elongation and that one copy of Jak1 can compensate for JAK2 deficiency. After the generation and assessment of quadruple STAT1/3/5a/5b mammary glands, we found that the combined deletion of STATs was not sufficient to block ductal development despite the lack of activation of all seven STATs. These results suggest that in addition to their discrete STAT-dependent functions during the gestational cycle, JAK2 and JAK1 have STAT-independent non-canonical functions that are essential for mammary gland ductal elongation. In this study, we also explored JAK/STAT signaling in two different murine triple-negative breast cancer models. Using a claudin-low mammary tumor model driven by mutant KRASG12D expression, we show that (1) JAK1 mediates the oncogenic activation of STAT3 in claudin-low breast cancers, (2) the simultaneous deletion of STAT3 and STAT5 prevents mammary tumor initiation, and (3) the loss of STAT3/5 in claudin-low mammary tumors leads to the same compensatory activation of STAT1 that we identified in the normal mammary epithelium. Additionally, we generated a murine model that overexpresses TSG101 leading to the development of triple-negative adenosquamous carcinomas. We also demonstrated that the perpetual expression of TSG101 is essential for cancer cell survival in established tumors. Moreover, we found that adenosquamous carcinomas show enriched signatures of cytokine interaction and JAK/STAT signaling. On the molecular level, these tumors expressed high activated levels of STAT3, STAT5, and an inactivation of STAT1. In summary, our studies uncovered novel cooperative and compensatory functions of JAKs and STATs proteins in both mammary gland development and breast cancer. We generated the first mouse model that is completely deficient in the expression and activation of all known STAT proteins. We also made the paradigm-shifting observation that important roles of JAK1/2 are mediated by noncanonical mechanisms that may or may not require their tyrosine kinase functions. The collective results of our experimental models also provide evidence that the co-targeting of STAT5 and STAT3, and potentially their upstream activators JAK1 and JAK2, may serve as a preventive or therapeutic strategy for the highly aggressive triple-negative breast cancer subtype.

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