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Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 31 August 2026 | Viewed by 7286

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Dr. Hisham Bahmad

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Department of Pathology and Laboratory Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
Interests: cancer stem cells; pathology; breast cancer; gynecologic cancer; molecular genetics; cancer biology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Breast and gynecologic cancers continue to pose significant global health burdens, accounting for substantial morbidity and mortality among women worldwide. Despite the progress in diagnostic and therapeutic strategies, challenges remain in predicting disease progression and patient outcomes. The rapid expansion of molecular pathology has provided valuable insights into the pathogenesis of these malignancies, highlighting the important role of genetic, epigenetic, and transcriptomic alterations in shaping the tumor behavior. This Special Issue, entitled “Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers,” aims to explore the interface between molecular pathology and clinical practice. We welcome contributions that identify novel biomarkers with diagnostic or prognostic value, as well as those that uncover emerging molecular targets with potential therapeutic applications. Particular emphasis will be placed on translational research that bridges the gap between molecular discoveries and real-world implementation in pathology and oncology. We invite researchers in molecular biology, cancer genomics, pathology, oncology, and related fields to submit original research articles, comprehensive reviews, and insightful perspectives that advance our understanding of breast and gynecologic cancers—including, but not limited to, breast, endometrial, ovarian, cervical, vaginal, vulvar, and fallopian tube carcinomas. We look forward to your valuable contributions to this timely and impactful Special Issue.

Dr. Hisham Bahmad
Guest Editor

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Keywords

cancer
uterus
cervix
breast
ovary
endometrial cancer
ovarian cancer
cervical cancer
breast cancer
biomarkers
therapeutic target
personalized medicine
targeted therapy
molecular signatures
diagnosis
prognosis

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Published Papers (6 papers)

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Research

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19 pages, 2642 KB

Open AccessArticle

Genome-Wide CRISPR Screens Identify ABCG2-Mediated Drug Resistance to the Threonine Tyrosine Kinase (TTK) Inhibitor CFI-402257 in Breast Cancer

by Kelsie L. Thu, Soode Jafari, Jennifer Silvester, Jennifer Cruickshank, Isabel Soria-Bretones, Kelsey Hodgson, Chantal Tobin, Jillian Haight, Asa P. Y. Lau, Tessa Bray, Drew Wakeham, Mark R. Bray, Tak W. Mak and David W. Cescon

Int. J. Mol. Sci. 2026, 27(6), 2665; https://doi.org/10.3390/ijms27062665 - 14 Mar 2026

Abstract

CRISPR screens are a powerful functional genomics approach for identifying genes that confer sensitivity and resistance to anti-cancer therapies. CFI-402257 (luvixasertib, 2257) is a small molecule inhibitor of threonine tyrosine kinase (TTK), a promising therapeutic target in genomically unstable cancers due to its critical role in establishing the spindle assembly checkpoint (SAC) during mitosis. To inform its ongoing development and evaluation in clinical trials, we sought to use CRISPR activation (i.e., gain of function) screens to identify cellular mechanisms of resistance to 2257 in models of triple-negative breast cancer (TNBC). In vitro screens conducted in two TNBC cell lines nominated ABCG2 as the top resistance-conferring gene in both models. Validation studies assessing clonogenic survival and apoptosis confirmed that ABCG2 overexpression enhanced TNBC resistance to 2257 in vitro, while knockdown enhanced sensitivity. These findings suggest that 2257 is a substrate of ABCG2’s drug efflux activity. However, overexpression of ABCG2 failed to confer resistance to 2257 in TNBC xenografts grown in mice and treated with a moderately active dose and schedule. Our results highlight the potential impact of drug transporters in in vitro CRISPR screens and the importance of confirming the relevance of drug response mechanisms identified in cultured cells using in vivo models that recapitulate drug pharmacokinetics and pharmacodynamics. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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22 pages, 10835 KB

Open AccessArticle

Reactive Stroma as a Transversal Prognostic Biomarker for Metastasis in Breast Cancer: Integration of Digital Histopathology and Transcriptomic Profiling

by Daniela P. Barrera, Muriel A. Núñez, Valentina Cerda I., J. Sebastián Contreras-Riquelme, Jenny Henríquez, Guillermo Carrasco, Alejandra Pereira, Vania Figueroa, Verónica Toledo, Badir Chahuan, Jorge Sapunar-Zenteno, Ximena Rodríguez, Daniel Moreno, José Tomás Larach, Benjamín Prieto, Patricia García, Leonor Moyano, José Peña and Javier Cerda-Infante

Int. J. Mol. Sci. 2026, 27(5), 2213; https://doi.org/10.3390/ijms27052213 - 26 Feb 2026

Viewed by 336

Abstract

Distant metastasis is the main cause of breast cancer (BC) mortality, yet current prognostic models remain largely tumor-centric and underutilize stromal biology. In this study, we quantified reactive stroma, a collagen-rich and fibrotic fraction of the stromal compartment, as a subtype-independent biomarker of metastatic risk. A retrospective cohort of 182 FFPE primary BC biopsies (2006–2020) was analyzed. Total stroma was quantified on H&E-stained sections and reactive stroma on Masson’s trichrome using QuPath with pathologist validation. Cutoffs were defined using maximally selected rank statistics, and overall survival (OS) and metastasis-free survival (MFS) were evaluated by Kaplan–Meier analysis and multivariable Cox regression. RNA sequencing was performed in a subset of cases to characterize associated transcriptomic programs. While total stromal content showed univariate associations with OS and MFS, it was not independently prognostic after adjustment. In contrast, high reactive stroma (cutoff 53.2%) independently predicted shorter MFS (HR = 3.76; p < 0.001), irrespective of molecular subtype and clinicopathological variables. Tumors with high reactive stroma exhibited upregulation of extracellular matrix and profibrotic genes (including FN1, OLR1, and EDN2), enrichment of collagen remodeling and TGF-β signaling pathways, and reduced T-cell activation signatures. These findings demonstrate that quantitative assessment of reactive stroma from standard histological stains is a reproducible, subtype-independent biomarker of metastatic risk in BC and can be readily integrated into routine pathology workflows to improve risk stratification. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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25 pages, 2811 KB

Open AccessArticle

The Genetic and Molecular Analyses of Rare Candidate Germline BRIP1/FANCJ Variants Implicated in Hereditary Breast and Ovarian Cancers

by Wejdan M. Alenezi, Larissa Milano, Caitlin T. Fierheller, Corinne Serruya, Timothée Revil, Kathleen K. Oros, Jeffrey P. Bruce, Dan Spiegelman, Trevor Pugh, Anne-Marie Mes-Masson, Diane Provencher, William D. Foulkes, Zaki El Haffaf, Guy Rouleau, Luigi Bouchard, Celia M. T. Greenwood, Jiannis Ragoussis, Jean-Yves Masson and Patricia N. Tonin

Int. J. Mol. Sci. 2026, 27(2), 1037; https://doi.org/10.3390/ijms27021037 - 20 Jan 2026

Viewed by 603

Abstract

Five rare variants in BRIP1/FANCJ, initially identified in ovarian cancer (OC) or breast cancer (BC) cases by the adult hereditary cancer clinics, were investigated for their candidacy as clinically relevant variants. These variants were investigated genetically in a population exhibiting genetic drift and molecularly assayed for biological impact. Using in silico tools, population-based genetic databases and other resources, three of the five reported BRIP1 variants were likely to be damaging: c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61. The carrier frequencies ranged from 0 to 0.7% in ancestry-defined cancer groups comprising 47 OC families, 49 hereditary breast and ovarian cancer syndrome families, 142 hereditary breast cancer syndrome families, 435 sporadic OC cases and 563 sporadic BC cases and 0–0.2% in 1025 population-matched controls. Multiple carriers of the these variants were identified in additional population-matched cancer cases. Of the five reported BRIP1 variants, p.Thr266Met, p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61, which were predicted to be damaging, conferred cellular sensitivity to mitomycin C and cisplatin unlike p.Ser139Ala and p.Ala406Ser. Collectively, our investigation implicates BRIP1 c.797C>T; p.Thr266Met, c.2087C>T; p.Pro696Leu and c.2990_2993delCAAA; p.Thr997ArgfsTer61 as deleterious variants in OC and BC. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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Review

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41 pages, 1270 KB

Open AccessReview

Decoding Breast Cancer: Emerging Molecular Biomarkers and Novel Therapeutic Targets for Precision Medicine

by Dámaris P. Intriago-Baldeón, Eduarda Sofía Pérez-Coral, Martina Isabella Armas Samaniego, Vanessa I. Romero, Juan Carlos Pozo Palacios and Gabriele Davide Bigoni-Ordóñez

Int. J. Mol. Sci. 2026, 27(1), 138; https://doi.org/10.3390/ijms27010138 - 22 Dec 2025

Viewed by 2156

Abstract

Breast cancer is the most frequent gynecological malignancy and the main cause of cancer death in the female population worldwide. One of the most significant challenges in its clinical management is the molecular heterogeneity of malignant breast tumors, which is reflected in the current molecular classification of these entities. In each of these tumor molecular subtypes, distinct genetic alterations are involved, and several intracellular signaling pathways contribute to defining their biological identity and clinical response. This literature review summarized the main classic and emerging biomarkers in breast cancer, along with the therapies associated with them. There are several classic biomarkers associated with this disease, such as estrogen and progesterone receptors, the HER2 receptor, and the Ki-67 cell proliferation marker. Given the limitations of these biomarkers, new biomarkers have been identified, including the TP53 tumor suppressor gene, the EGFR, different types of RNAs, plus epigenetic and immunological biomarkers. The integration of classic and emerging biomarkers along with new therapeutic targets in the clinical practice has promoted a thorough understanding of the high molecular complexity of breast cancer and the development of precision medicine strategies which increase the chances of therapeutic success. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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33 pages, 1320 KB

Open AccessReview

Fueling the Seed: Growth Factors and Cytokines Driving Cancer Stem Cells in Gynecological Malignancies

by Alessandro Sarcinella, Juan Sebastian Guerra Villacis and Maria Felice Brizzi

Int. J. Mol. Sci. 2025, 26(23), 11462; https://doi.org/10.3390/ijms262311462 - 26 Nov 2025

Cited by 1 | Viewed by 1121

Abstract

Gynecological cancers remain a major global health burden due to their high incidence, molecular heterogeneity, and frequent resistance to conventional therapies. Beyond well-established genetic alterations and targeted treatments, growing attention has been directed toward the role of cancer stem cells (CSCs), a rare tumor subpopulation with self-renewal, differentiation, and tumor-initiating capacities. CSCs are sustained by a specialized microenvironment, the cancer stem cell niche, where growth factors, cytokines, hypoxia, and stromal interactions converge to promote stemness, chemoresistance, and metastatic potential. In breast cancer, signaling axes such as EGFR, IGF, TGFβ, and HGF/c-Met critically regulate CSC expansion, particularly in aggressive subtypes like triple-negative tumors. In ovarian cancer, factors including HGF, VEGFA, IGF, and stromal-derived BMPs drive CSC plasticity and contribute to relapse after platinum therapy. Endometrial CSCs are supported by pathways involving TGFβ, BMP2, and Netrin-4/c-Myc signaling, while in cervical cancer, VEGF, IGF-1, Gremlin-1, and TGFβ-mediated circuits enhance stem-like phenotypes and drug resistance. Cytokine-driven inflammation, especially via IL-3, IL-6, IL-8, IL-10, and CCL5, further fosters CSC survival and immune evasion across gynecologic malignancies. Preclinical studies demonstrate that targeting growth factors and cytokine signaling, through monoclonal antibodies, receptor inhibitors, small molecules, or cytokine modulation, can reduce CSC frequency, restore chemosensitivity, and enhance immunotherapy efficacy. This review highlights the interplay between CSCs, growth factors, and cytokines as central to tumor progression and relapses, emphasizing their translational potential as therapeutic targets in precision oncology for gynecological cancers. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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24 pages, 2208 KB

Open AccessReview

Beyond the Microscope: Integrating Liquid Biopsies into the Molecular Pathology Era of Endometrial Cancer

by Miguel Perez, Luis Lorenzo Carvajal, Andres Wong, Robert Poppiti, Roberto Ruiz-Cordero, Amilcar A. Castellano-Sánchez and Hisham F. Bahmad

Int. J. Mol. Sci. 2025, 26(16), 7987; https://doi.org/10.3390/ijms26167987 - 19 Aug 2025

Viewed by 2631

Abstract

Endometrial cancer (EC) is the most common gynecologic malignancy in developed countries, with a growing incidence and significant molecular heterogeneity that challenges traditional diagnostic and management paradigms. While histopathological assessment remains the gold standard for diagnosis, emerging liquid biopsy technologies provide promising non-invasive alternatives for tumor detection, molecular profiling, and disease monitoring. This review comprehensively explores the current landscape and clinical utility of liquid biopsy analytes—including circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), cell-free DNA (cfDNA), extracellular RNAs, and exosomes—in the context of EC. We discuss the evolving role of pathologists in integrating molecular data with histomorphological features to enhance diagnostic precision, prognostic stratification, and therapeutic decision-making. Novel technologies such as methylation-based assays, tumor-informed ctDNA sequencing, and tumor-educated platelets (TEPs) are highlighted for their diagnostic accuracy and potential for early detection. Furthermore, we summarize key clinical trials and future directions aimed at validating liquid biopsy platforms for routine clinical implementation. As EC care transitions toward a precision oncology model, the integration of liquid biopsy with traditional surgical pathology offers a transformative approach to individualized and personalized patient management. Full article

(This article belongs to the Special Issue Novel Biomarkers and Emerging Therapeutic Targets for Breast and Gynecologic Cancers)

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