Padmashree Rida

Ductal carcinoma in situ (DCIS) is a non-invasive precursor to invasive breast cancer. DCIS incidence continues to rise, yet its clinical management remains constrained by the absence of reliable biomarkers that can adequately distinguish indolent lesions from those with high invasive potential, to circumvent over- or under-treatment. Black women with DCIS are significantly more likely to progress to invasive breast cancer, are disproportionately diagnosed with high-grade, hormone receptor-negative lesions, and experience elevated risk of recurrence and mortality relative to White women with DCIS. These disparities persist despite comparable access to screening and treatment, suggesting underlying biological and tissue microenvironmental factors. This review synthesizes emerging evidence implicating early molecular and systemic changes that may be driving the disparity in DCIS progression. We highlight racial distinctions in interconnected pathways involving Wnt/β-catenin signaling, metabolic and nutritional dysregulation, immune microenvironment remodeling, and cellular tolerance of genomic instability. We further discuss how epigenetic alterations, obesity-associated inflammation, and immune dysregulation may arise during the pre-invasive stage that intersect with social and environmental exposures to influence racial differences in lesion fate. We spotlight candidate biomarkers disproportionately associated with aggressive disease in Black women—including KIFC1, a mediator of centrosome clustering and genomic instability tolerance, and ACKR1/DARC, a regulator of chemokine gradients and immune trafficking—as potential drivers of progression-permissive states. This review advances an integrated, equity-informed framework for DCIS progression that links early tumor evolution to coordinated alterations in genomic instability, immune regulation, metabolic signaling, and stress-adaptive pathways. Importantly, we propose that DCIS progression is governed not by isolated molecular alterations but by coordinated programs that enable survival under genomic and immunologic stress. Current clinical risk assays, which primarily capture tumor-intrinsic proliferation and hormone signaling, do not fully resolve these pathways and may therefore incompletely reflect biologically meaningful racial disparities. This synthesis underscores the need for pathway-level, microenvironment-informed, and population-representative approaches to DCIS risk stratification. Advancing such frameworks will be essential for identifying actionable biomarkers, refining early intervention strategies, and ultimately reducing racial disparities in breast cancer outcomes.

The United States faces a worsening maternal mortality crisis that starkly contrasts with trends in other high-income nations. Maternal mortality rates (MMRs) have more than doubled over the past two decades, rising from 9.65 deaths per 100,000 live births in 1999–2002 to 23.6 in 2018–2021, with approximately 700 deaths annually. Black and American Indian/Alaska Native women experience maternal mortality rates two to three times higher than their White counterparts, reflecting persistent structural inequities rather than biological differences. This narrative review synthesizes current evidence on the underlying drivers of racial inequities in maternal mortality and evaluates evidence-based interventions and policy strategies to address these disparities. A comprehensive literature review between 2000 and 2025 was conducted using databases including PubMed, Scopus, Web of Science, and Google Scholar, focusing on studies examining clinical, social, and structural determinants of maternal health outcomes, as well as evidence-based interventions and maternal health policy. Targeted searches of policy reports and grey literature were also performed to identify relevant policy initiatives and system-level interventions. Key contributors to disparities include underlying health conditions, postpartum mental health inequities, provider shortages, and limited access to postpartum care, with pregnancy-associated breast cancer (PABC) representing a less common but clinically significant risk factor that warrants further investigation in the context of racial inequities. Structural racism and socioeconomic disparities further exacerbate inequities through differential access to care, treatment bias, and barriers to healthcare utilization. System-level challenges, including workforce shortages, maternity care deserts, and the absence of federally mandated paid maternity leave, disproportionately impact marginalized populations. Although policy initiatives such as Medicaid postpartum coverage extensions, the Maternal Health Momnibus Act, and Maternal Mortality Review Committees represent important progress, they remain insufficient without broader structural reform. Evidence-based interventions, including midwife- and doula-led care, community-based peer support, and culturally tailored mental health programs, demonstrate measurable improvements in maternal outcomes. Outcomes of this review highlight the need for a comprehensive, equity-centered approach to reducing maternal mortality disparities, emphasizing structural reform, expanded access to care, strengthened data systems, and community-driven solutions.

Although ductal carcinoma in situ (DCIS) diagnoses continue to climb, patient management remains constrained by limitations in recurrence prediction. Conventional histopathology and existing prognostic parameters often inadequately predict local recurrence, leading to over- or under-treatment. Additionally, discourse remains over the clinical implications of margin width as a measure of recurrence risk, demonstrating the limitations of a margin-based model, and motivating our proposal that recurrence risk is dynamic and should be defined by patient-specific, spatially resolved diagnostic biomarkers. This review introduces field cancerization as a framework that may illuminate mechanisms underlying DCIS ipsilateral recurrence and improve clinical decision-making. We propose that the potential drivers of ductal field cancerization span two stages: pre-tumorigenesis and post-tumorigenesis. Pre-tumorigenic events include non-biological and biological exposome factors. Post-tumorigenic drivers include intratumoral and microenvironment-mediated remodeling of adjacent tissues that promote malignancy. This review bridges stage-specific molecular mechanisms to potentially actionable strategies for DCIS patient management—particularly margin assessment and recurrence risk prognostication—while highlighting the critical unmet need to identify biomarkers that measure high-risk field changes. We also emphasize the need to move beyond lesion-centric management toward multivariable prognostic models that include distance-mapped field biomarkers, enabling more precise surgery, improved selection of adjuvant therapy, and safer de-escalation for low-risk patients.

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.

There are currently no approved targeted treatments for quadruple-negative breast cancer [QNBC; ER⁻/PR⁻/HER2⁻/androgen receptor (AR)⁻], a subtype of triple-negative breast cancer (TNBC). AR-low TNBC is more proliferative and clinically aggressive than AR-high TNBC. Centrosome amplification (CA), a cancer hallmark, is rampant in TNBC, where it induces spindle multipolarity-mediated cell death unless centrosome clustering pathways are co-upregulated to avert these sequelae. We recently showed that genes that confer CA and centrosome clustering are strongly overexpressed in AR-low TNBCs relative to AR-high TNBCs. However, the molecular mechanisms that index centrosome clustering to the levels of CA are undefined. We argue that FOXM1, a cell cycle-regulated oncogene, links the expression of genes that drive CA to the expression of genes that act at kinetochores and along microtubules to facilitate centrosome clustering. We provide compelling evidence that upregulation of the FOXM1-E2F1-ATAD2 oncogene triad in AR-low TNBC is accompanied by CA and the co-upregulation of centrosome clustering proteins such as KIFC1, AURKB, BIRC5, and CDCA8, conferring profound dysregulation of cell cycle controls. Targeting FOXM1 in AR-low TNBC may render cancer cells incapable of clustering their centrosomes and impair their ability to generate excess centrosomes. Hence, our review illuminates FOXM1 as a potential actionable target for AR-low TNBC.

Quadruple-negative breast cancer (QNBC) lacks traditional actionable targets, including androgen receptor (AR). QNBC disproportionately afflicts and impacts patients of African genetic ancestry. Kinesin family member C1 (KIFC1/HSET), a centrosome clustering protein that prevents cancer cells from undergoing centrosome-amplification-induced apoptosis, has been reported to be upregulated in TNBCs and African-American (AA) TNBCs. Herein, we analyzed KIFC1 RNA levels and their associations with clinical features and outcomes among AR-low and AR-high TNBC tumors in three distinct publicly available gene expression datasets and in the breast cancer gene expression database (bc-GenExMiner). KIFC1 levels were significantly higher in AR-low and basal-like TNBCs than in AR-high and non-basal-like TNBCs, irrespective of the stage, grade, tumor size, and lymph node status. KIFC1 levels were also upregulated in AR-low tumors relative to AR-high tumors among Black and premenopausal women with TNBC. High KIFC1 levels conferred significantly shorter overall survival, disease-free survival, and distant metastasis-free survival among AR-low and basal-like TNBC patients in Kaplan–Meier analyses. In conclusion, KIFC1 levels may be upregulated in AR-low tumors and, specifically, in those of African descent, wherein it may promote poor outcomes. KIFC1 may be an actionable cancer-cell-specific target for the AR-low TNBC subpopulation and could aid in alleviating racial disparities in TNBC outcomes.