Overexpression of Proteins Involved in Mitotic Progression Underlies High Proliferation and Chromosomal Instability in Androgen Receptor-Low Triple-Negative Breast Cancer

Triple-negative breast cancer (TNBC), particularly the androgen receptor–low (AR-low) subtype, is one of the most aggressive and hard-to-treat forms of breast cancer, characterized by high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel intra-tumoral heterogeneity, therapy resistance, and poor clinical outcomes. An integrated framework that encompasses the dysregulated molecular networks and pathways that support the pathobiology of and shape AR-low TNBC has been lacking. In this data-supported review, we synthesize transcriptomic, epigenetic, and mechanistic evidence to show that AR-low and TP53-mutant breast cancers consistently upregulate mitotic kinesin motors, centromeric proteins, and regulators of proteolysis. These modules normally facilitate mitosis and safeguard genomic integrity, but when persistently and excessively activated, they promote unbridled proliferation while undermining fidelity of mitosis. The result is a paradoxical tumor state: rapid proliferation coupled with persistent mitotic errors, CIN, and aneuploidy, which in turn accelerate tumor evolution and adaptation. We propose a unifying model in which a FoxM1–WDR5–ASPM regulatory axis acts as a central driver of this dysregulation. In the absence of AR signaling, this axis locks tumor cells into a hyperproliferative state with cells traversing highly error-prone mitoses. This state involves a steep upregulation of mitotic kinesins, centromeric proteins, and regulators of protein degradation, fueling CIN and intra-tumoral heterogeneity. Loss of TP53 function fuels this dysregulation, and also allows the aneuploid cells to survive and continue dividing, perpetuating the aneuploid state. We also show that breast tumor overexpressing mitotic kinesins, centromeric proteins, and regulators of protein degradation, show characteristic infiltration patterns of immune and stromal cells in their tumor microenvironment, which could impact their prognosis and response to treatments. This perspective highlights how AR-low TNBC and TP53-mutant breast cancers bend core cell cycle machinery to sustain aggressive growth and evolve dynamically. By defining this interconnected regulatory network, we identify a set of actionable vulnerabilities with therapeutic potential and provide a framework for rethinking how to manage high proliferation, genomically unstable breast cancers.