Author ORCID Identifier

https://orcid.org/0000-0003-3688-5376

Semester

Summer

Date of Graduation

2026

Document Type

Dissertation

Degree Type

PhD

College

School of Medicine

Department

Biochemistry

Committee Chair

J. Michael Ruppert

Committee Member

Emidio Pistilli

Committee Member

Timothy Eubank

Committee Member

Bradley Webb

Committee Member

Gangqing Hu

Abstract

ABSTRACT

Nuclear AURKA-driven early dissemination of breast cancer uncovers opposing roles of HIF-1A and HIF-1B in metastasis.

Abha Maskey

Metastatic progression is the primary cause of mortality in the majority of solid tumors, including breast cancer (BC). The triple-negative breast cancer (TNBC) is the most aggressive BC subtype with the highest recurrence rates within 1-3 years post-diagnosis, and worst overall survival outcomes. Early distant recurrence of cancer is enabled by early disseminated tumor cells (eDTCs), yet the mechanisms of early dissemination remain poorly defined. Hypoxia-inducible factor 1 (HIF1) is a transcription factor normally induced under hypoxia to enable cell survival. It is the major cause of metastasis from hypoxic tumors. In our work, we demonstrated that the nuclear Aurora kinase A (N-AURKA) protein activates HIF1 under oxygenated conditions (oxHIF1) and induces dissemination from early-stage tumors (eDTCs). These eDTCs can be found in multiple distant organs and produce highly proliferative metastases in preclinical models. Mechanistically, we show that N-AURKA activates the HIF1 transcriptome by shifting the balance toward recruitment of the HIF1A and HIF1B subunits to form the HIF1 complex, thereby limiting other transcription factors, such as AHR, that also require HIF1B/ARNT. In agreement with previous reports, HIF1A depletion significantly reduced metastatic burden, whereas HIF1B depletion dramatically increased the metastatic burden by heightening both dissemination and colonization at distant sites. HIF1B/ARNT deficiency reveals a previously unrecognized function of HIF1B as a metastasis suppressor. We uncovered the opposing roles HIF1 subunits play in the metastatic process. Genome-wide transcriptomic profiling demonstrates that HIF1B deficiency increases the expression of genes promoting cell motility, extracellular matrix degradation, and immune evasion, thereby facilitating metastasis, whereas HIF1A deficiency induces the expression of genes related to cell differentiation and the establishment of epithelial identity, and strengthens apical/basal adhesions, thereby inhibiting metastasis. Single-cell RNA sequencing of primary human TNBC tumors confirms that HIF1A-high/ARNT-low and HIF1A-low/ARNT-high tumor cell subpopulations co-exist within individual patient tumors and recapitulate these opposing transcriptional programs identified in our work. The ARNT-low/HIF1A-high state specifically predicts poor overall survival in the basal breast cancer subtype. The combination of drugs targeting HIF1 and cell proliferation blocks outgrowth of already disseminated eDTCs. It halts further cancer spread, resulting in a significant reduction in distant recurrence in preclinical models of TNBC.

These findings establish the N-AURKA/HIF1 axis as a driver of early metastatic dissemination in TNBC, reveal that HIF1A and HIF1B exert opposing subunit-specific control over the metastatic process, and identify a therapeutic window for suppressing early metastasis in TNBC.

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