Benecia Jackson

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 BC, characterized by a high index of proliferation, chromosomal instability (CIN), and high prevalence of TP53 mutations. These features fuel therapy resistance, metastases, and poor clinical outcomes. An integrated framework describing the dysregulated molecular networks that support the pathobiology of AR-low TNBC is lacking. Multiple published studies in breast cancer have previously proposed mechanistic links between TP53 loss, AR-low states, and heightened FOXM1-driven G2/M transcriptional programs, potentially via deregulation of E2F activity, chromatin-associated co-regulators (e.g., ATAD2), and disruption of repressive networks involving p53–p21–DREAM and SPDEF. Additional reports suggest that FOXM1-associated circuitry may be reinforced by chromatin regulators such as WDR5 and by mitotic/spindle factors such as ASPM, including through feedback interactions and condensate-associated transcriptional organization. We previously showed that FOXM1, a master regulator transcription factor, is upregulated and is a biomarker of poor prognosis in AR-low TNBC. In this study, we filtered a set of “TNBC core genes” known to promote transcriptional chaos downstream of FoxM1. We identified a set of 15 cell cycle regulators—including mitotic kinesin motors (KIF14, KIF11, KIF4A, KIF2C, and KIF20A), centromeric proteins (CENPA, CENPO, CENPL, CENPF, and OIP5), and regulators of proteolysis (UBE2C, UBE2S, UBE2T, PSMD14, and TUBA1B). These 15 genes, which were ranked highly among genes overexpressed in TNBC featured prominently in gene signatures of chromosomal instability and were also overexpressed among AR-low TNBCs and TP53-mutant breast tumors. We show that expression of each of these 15 genes correlates positively with proliferation markers (Ki67, PCNA, and MCM2) in TNBC, and that the overexpression of this gene set is associated with shorter relapse-free survival and distinct immune/stromal infiltration patterns. In light of prior work, our findings point to a FOXM1-associated 15-gene signature enriched in AR-low TNBC and associated with the high-proliferation and high-CIN phenotypes of this clinically challenging tumor type. This 15-gene set represents an actionable vulnerability with therapeutic potential for AR-low TNBC and provides a framework for rethinking how to manage highly proliferative, genomically unstable BCs.

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.