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18 pages, 5704 KiB

Open AccessArticle

Synergistic Effect of Ribitol and Shikonin Promotes Apoptosis in Breast Cancer Cells

by Ravi Doddapaneni, Jason D. Tucker, Pei J. Lu and Qi L. Lu

Int. J. Mol. Sci. 2025, 26(6), 2661; https://doi.org/10.3390/ijms26062661 - 15 Mar 2025

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Abstract

The mortality rate of breast cancer remains high, despite remarkable advances in chemotherapy. Therefore, it is imperative to identify new treatment options. In the present study, we investigated whether the metabolite ribitol enhances the cytotoxic effect of shikonin against breast cancer in vitro. [...] Read more.

The mortality rate of breast cancer remains high, despite remarkable advances in chemotherapy. Therefore, it is imperative to identify new treatment options. In the present study, we investigated whether the metabolite ribitol enhances the cytotoxic effect of shikonin against breast cancer in vitro. Here, we screened a panel of small molecules targeting energy metabolism against breast cancer. The results of the study revealed that ribitol enhances shikonin’s growth-inhibitory effects, with significant synergy. A significant (p < 0.01) increase in the percentage (56%) of apoptotic cells was detected in the combined treatment group, compared to shikonin single-treatment group (38%), respectively. The combined ribitol and shikonin treatment led to significant arrest of cell proliferation (40%) (p < 0.01) compared to untreated cells, as well as the induction of apoptosis. This was associated with upregulation of p53 (p < 0.05) and downregulation of c-Myc (p < 0.01), Bcl-xL (p < 0.001), and Mcl-1 (p < 0.05). Metabolomic analysis supports the premise that inhibition of the Warburg effect is involved in shikonin-induced cell death, which is likely further enhanced by dysregulation of glycolysis and the tricarboxylic acid (TCA) cycle, afflicted by ribitol treatment. In conclusion, the present study demonstrates that the metabolite ribitol selectively enhances the cytotoxic effect mediated by shikonin against breast cancer in vitro. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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17 pages, 3136 KiB

Open AccessArticle

Two-Step Cell Death Induction by the New 2-Arachidonoyl Glycerol Analog and Its Modulation by Lysophosphatidylinositol in Human Breast Cancer Cells

by Mikhail G. Akimov, Natalia M. Gretskaya, Evgenia I. Gorbacheva, Nisreen Khadour, Galina D. Sherstyanykh and Vladimir V. Bezuglov

Int. J. Mol. Sci. 2025, 26(2), 820; https://doi.org/10.3390/ijms26020820 - 19 Jan 2025

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Abstract

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types of tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, ceramide is counterbalanced by the sphingosine-1-phosphate, [...] Read more.

2-arachnadoyl glycerol (2-AG) is one of the most common endocannabinoid molecules with anti-proliferative, cytotoxic, and pro-proliferative effects on different types of tumors. Typically, it induces cell death via cannabinoid receptor 1/2 (CB1/CB2)-linked ceramide production. In breast cancer, ceramide is counterbalanced by the sphingosine-1-phosphate, and thus the mechanisms of 2-AG influence on proliferation are poorly understood. We evaluated the mechanism of the anti-proliferative action by 2-AG and the influence of lysophaosphatidylinositol (LPI) on it in six human breast cancer cell lines of different tumor degree (MCF-10A, MCF-7, BT-474, BT-20, SK-BR-3, and MDA-MB-231) using resazurin test, inhibitor, blocker, and anti-oxidant analysis, and siRNA interference. To avoid acyl migration in 2-AG, we replaced it with the analog 2-arachidonoyl-1,3-difluoropropanol (2-ADFP) newly synthesized by us. Using a molecular docking approach, we showed that at the CB2 receptor, 2-ADFP and 2-AG were very close to each other. However, 2-ADFP demonstrated a stronger affinity towards CB1 in the antagonist-bound conformation. 2-ADFP was anti-proliferative in all the cell lines tested. The toxicity of 2-ADFP was enhanced by LPI. 2-ADFP activity was reduced or prevented by the CB2 and vanilloid receptor 1 (TRPV1) blockers, inositol triphosphate receptor, CREB, and cyclooxygenase 2 inhibitor, and by anti-oxidant addition. Together with the literature data, these results indicate CB2- and TRPV1-dependent COX-2 induction with concomitant cell death induction by the oxidized molecule’s metabolites. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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9 pages, 857 KiB

Open AccessCommunication

Neoadjuvant Chemotherapy for T3 Tumors in the Era of Precision Medicine—Biology Is Still King

by Rakhshanda Layeequr Rahman, Alfredo Santillan, Mehran Habibi, Peter Beitsch, Pat Whitworth, Harshini Ramaswamy, Nicole Chmielewski-Stivers, Andrea Menicucci, William Audeh and Joyce O’Shaughnessy

Int. J. Mol. Sci. 2025, 26(2), 491; https://doi.org/10.3390/ijms26020491 - 9 Jan 2025

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Abstract

Clinical T3 (cT3) breast cancer (BC) presents a challenge for achieving cosmetically acceptable breast conservation, and neoadjuvant chemotherapy (NAC) is commonly used for cytoreduction in these high-risk cancers. MammaPrint^® risk-of-recurrence and BluePrint^® molecular subtyping genomic signatures have demonstrated high accuracy in [...] Read more.

Clinical T3 (cT3) breast cancer (BC) presents a challenge for achieving cosmetically acceptable breast conservation, and neoadjuvant chemotherapy (NAC) is commonly used for cytoreduction in these high-risk cancers. MammaPrint^® risk-of-recurrence and BluePrint^® molecular subtyping genomic signatures have demonstrated high accuracy in predicting chemotherapy benefits. Here, we examined the utility of MammaPrint/BluePrint for predicting pathological Complete Response (pCR) rates to NAC among 404 patients diagnosed with cT3 early-stage BC. The association of genomic subtype and clinical features with the likelihood of pCR was evaluated by multivariate logistic regression. Differences in pCR rates between genomic risk categories were evaluated by a two-sided proportional z-test and stratified by nodal status. MammaPrint/BluePrint subtyping was associated with significantly higher odds ratios (ORs) for pCR in MammaPrint High-Risk/BluePrint Basal-Type (OR = 3.06, 95% CI: 1.15–8.19, p = 0.025) and HER2-Type (OR = 6.27, 95% CI: 2.19–19.38, p = 0.001) compared to BluePrint Luminal-Type. Of the 209 patients with hormone receptor-positive, HER2-negative disease, 6.7% achieved pCR, and MammaPrint High-Risk was associated with a significantly higher pCR rate (9.3%) compared to MammaPrint Low-Risk cancers (0%), regardless of nodal involvement (p = 0.036). These data show that for patients with MammaPrint Low-Risk, cT3 tumors are less likely to have clinically impactful cytoreduction from NAC, regardless of nodal involvement. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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22 pages, 9046 KiB

Open AccessArticle

Single-Sample Networks Reveal Intra-Cytoband Co-Expression Hotspots in Breast Cancer Subtypes

by Richard Ponce-Cusi, Patricio López-Sánchez, Vinicius Maracaja-Coutinho and Jesús Espinal-Enríquez

Int. J. Mol. Sci. 2024, 25(22), 12163; https://doi.org/10.3390/ijms252212163 - 13 Nov 2024

Cited by 1 | Viewed by 1127

Abstract

Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this [...] Read more.

Breast cancer is a heterogeneous disease comprising various subtypes with distinct molecular characteristics, clinical outcomes, and therapeutic responses. This heterogeneity evidences significant challenges for diagnosis, prognosis, and treatment. Traditional genomic co-expression network analyses often overlook individual-specific interactions critical for personalized medicine. In this study, we employed single-sample gene co-expression network analysis to investigate the structural and functional genomic alterations across breast cancer subtypes (Luminal A, Luminal B, Her2-enriched, and Basal-like) and compared them with normal breast tissue. We utilized RNA-Seq gene expression data to infer gene co-expression networks. The LIONESS algorithm allowed us to construct individual networks for each patient, capturing unique co-expression patterns. We focused on the top 10,000 gene interactions to ensure consistency and robustness in our analysis. Network metrics were calculated to characterize the topological properties of both aggregated and single-sample networks. Our findings reveal significant fragmentation in the co-expression networks of breast cancer subtypes, marked by a change from interchromosomal (TRANS) to intrachromosomal (CIS) interactions. This transition indicates disrupted long-range genomic communication, leading to localized genomic regulation and increased genomic instability. Single-sample analyses confirmed that these patterns are consistent at the individual level, highlighting the molecular heterogeneity of breast cancer. Despite these pronounced alterations, the proportion of CIS interactions did not significantly correlate with patient survival outcomes across subtypes, suggesting limited prognostic value. Furthermore, we identified high-degree genes and critical cytobands specific to each subtype, providing insights into subtype-specific regulatory networks and potential therapeutic targets. These genes play pivotal roles in oncogenic processes and may represent important keys for targeted interventions. The application of single-sample co-expression network analysis proves to be a powerful tool for uncovering individual-specific genomic interactions. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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13 pages, 2903 KiB

Open AccessArticle

In-Depth Analysis of the Peripheral Immune Profile of HER2+ Breast Cancer Patients on Neoadjuvant Treatment with Chemotherapy Plus Trastuzumab Plus Pertuzumab

by Ayelén Ivana Pesce Viglietti, María Belén Bordignon, Alexis Ostinelli, Manglio Miguel Rizzo, Gerardo Cueto, María Belén Sanchez, Florencia Perazzo, Mora Amat, Federico Coló, María Victoria Costanzo, Adrián Nervo, Jorge Nadal, Gabriel Crimi, Ignacio Mc Lean, Eunice Amancay Spengler, José Mordoh, Pablo Mandó and Estrella Mariel Levy

Int. J. Mol. Sci. 2024, 25(17), 9268; https://doi.org/10.3390/ijms25179268 - 27 Aug 2024

Viewed by 1712

Abstract

Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association [...] Read more.

Currently, therapy for early-stage human epidermal growth factor receptor 2-positive (HER2+) breast cancer (BC) is based on the combination of trastuzumab and pertuzumab plus chemotherapy in a neoadjuvant regimen. The INMUNOHER study aimed to detect immunological markers in peripheral blood and their association with treatment response. Sixty-two HER2+ BC patients were recruited. Pre-treatment samples were obtained before the start of treatment, while post-treatment samples were obtained after completing therapy and before surgery and were analyzed by flow cytometry. The pathologic complete response (pCR) rate achieved was 82.3%. The expression of the NKp30, PD-1, and TIM-3 receptors was reduced in the Natural Killer (NK)-CD56dim subset of patients who did not achieve pCR. Following therapy, many changes were found in leukocytes, including alterations in T cell lymphocyte proportions. Also, the percentage of NK cells decreased, and several phenotypic changes were observed in this population. After treatment, IFN-γ production by NK cells against HER2+-cells with or without trastuzumab was significantly reduced. HER2-targeted therapy plus chemotherapy demonstrated high efficacy in most patients, reducing the statistical power for finding immunological markers. However, NK subset phenotypes correlated better with response groups, and numerous changes in the percentage of leukocytes and T and NK cells, as well as changes in the functionality of NK cells, were observed in most patients after treatment, encouraging further research into these immune populations. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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12 pages, 1802 KiB

Open AccessArticle

Comparing the HER2 Status of the Primary Tumor to That of Disseminated Tumor Cells in Early Breast Cancer

by Léa Louise Volmer, Dominik Dannehl, Sabine Matovina, Florin-Andrei Taran, Christina Barbara Walter, Markus Wallwiener, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Tobias Engler

Int. J. Mol. Sci. 2024, 25(11), 5910; https://doi.org/10.3390/ijms25115910 - 29 May 2024

Viewed by 1393

Abstract

Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors [...] Read more.

Breast cancer remains a leading cause of cancer mortality in women globally. Despite advancements in systemic therapy, the risk of distant recurrence persists even after such treatment and may be linked to disseminated tumor cells (DTCs). Variability in molecular characteristics between primary tumors (PTs) and distant metastases underscores the need to comprehensively understand metastatic pathways. This retrospective study investigated discrepancies between HER2 expression in PTs and DTCs and their implications for survival outcomes in 201 early breast cancer (EBC) patients. We found a significant association between HER2 expression in PTs and DTCs when classifying tumors as HER2-high/low/negative. Patients whose HER2 status was discordant between PTs and DTCs exhibited worse distant disease-free survival than those with concordant status. Multivariate analysis confirmed the HER2 status of DTCs as an independent prognostic factor for distant DFS. These findings emphasize the importance of assessing HER2 expression in DTCs and its potential implications for tailored therapy strategies in EBC. Furthermore, prospective trials are needed to validate these findings and explore targeted therapies based on the molecular characteristics of DTCs. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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23 pages, 3059 KiB

Open AccessArticle

Tamoxifen Activates Transcription Factor EB and Triggers Protective Autophagy in Breast Cancer Cells by Inducing Lysosomal Calcium Release: A Gateway to the Onset of Endocrine Resistance

by Cecilia Boretto, Chiara Actis, Pawan Faris, Francesca Cordero, Marco Beccuti, Giulio Ferrero, Giuliana Muzio, Francesco Moccia and Riccardo Autelli

Int. J. Mol. Sci. 2024, 25(1), 458; https://doi.org/10.3390/ijms25010458 - 29 Dec 2023

Cited by 5 | Viewed by 2141

Abstract

Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal [...] Read more.

Among the several mechanisms accounting for endocrine resistance in breast cancer, autophagy has emerged as an important player. Previous reports have evidenced that tamoxifen (Tam) induces autophagy and activates transcription factor EB (TFEB), which regulates the expression of genes controlling autophagy and lysosomal biogenesis. However, the mechanisms by which this occurs have not been elucidated as yet. This investigation aims at dissecting how TFEB is activated and contributes to Tam resistance in luminal A breast cancer cells. TFEB was overexpressed and prominently nuclear in Tam-resistant MCF7 cells (MCF7-TamR) compared with their parental counterpart, and this was not dependent on alterations of its nucleo-cytoplasmic shuttling. Tam promoted the release of lysosomal Ca²⁺ through the major transient receptor potential cation channel mucolipin subfamily member 1 (TRPML1) and two-pore channels (TPCs), which caused the nuclear translocation and activation of TFEB. Consistently, inhibiting lysosomal calcium release restored the susceptibility of MCF7-TamR cells to Tam. Our findings demonstrate that Tam drives the nuclear relocation and transcriptional activation of TFEB by triggering the release of Ca²⁺ from the acidic compartment, and they suggest that lysosomal Ca²⁺ channels may represent new druggable targets to counteract the onset of autophagy-mediated endocrine resistance in luminal A breast cancer cells. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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12 pages, 866 KiB

Open AccessArticle

The Clinical Relevance of the NATALEE Study: Application of the NATALEE Criteria to a Real-World Cohort from Two Large German Breast Cancer Centers

by Henning Schäffler, Franziska Mergel, Kerstin Pfister, Stephan Lukac, Angelina Fink, Kristina Veselinovic, Brigitte Rack, Visnja Fink, Elena Leinert, Moritz Dimpfl, Alexander Englisch, Christian Martin Tegeler, Anna Seller, Eva-Maria Grischke, Markus Hahn, Léa Louise Volmer, Tobias Engler, Marie Louise Frevert, Florin Andrei Taran, Wolfgang Janni, Sara Yvonne Brucker, Andreas Daniel Hartkopf and Dominik Dannehl Show full author list Hide full author list

Int. J. Mol. Sci. 2023, 24(22), 16366; https://doi.org/10.3390/ijms242216366 - 15 Nov 2023

Cited by 14 | Viewed by 5175

Abstract

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective [...] Read more.

The NATALEE study showed a significant benefit in invasive disease-free survival (iDFS) for patients with HR+/HER2− early breast cancer (eBC) at intermediate and high risk of recurrence who were treated with the CDK4/6 inhibitor Ribociclib in combination with endocrine therapy (ET). This retrospective study aims to apply the NATALEE inclusion criteria to a representative real-world cohort to estimate the proportion of HR+/HER2− breast cancer patients eligible for adjuvant Ribociclib therapy. Patients who underwent full surgical treatment for eBC between January 2018 and December 2020 at two large German university breast cancer centers (University of Ulm, University of Tuebingen) were included. Descriptive statistics were used to characterize the patient population eligible for Ribociclib treatment based on the NATALEE study’s inclusion criteria. Out of 2384 enrolled patients, 1738 had HR+/HER2− eBC, of whom 43% (747/1738) met the NATALEE inclusion criteria. Of note, these patients were older, received less chemotherapy and presented with less advanced tumor stages compared to the NATALEE study cohort. Additionally, compared to the NATALEE study cohort, fewer patients had lymph node involvement (72.4% vs. 88.7%). Our analysis suggests that approximately 43% of all HR+/HER2− breast cancer patients will qualify for Ribociclib treatment. Given the numerous treatment options for patients with HR+/HER2− eBC, as well as the differences between the NATALEE cohort and patients in the real-world clinical setting, future analyses will be needed to determine which patients would benefit most from adjuvant CDK4/6 inhibitor treatment. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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Review

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18 pages, 307 KiB

Open AccessReview

Immunotherapy in Breast Cancer: Beyond Immune Checkpoint Inhibitors

by Yeonjoo Choi, Jiayi Tan, David Lin, Jin Sun Lee and Yuan Yuan

Int. J. Mol. Sci. 2025, 26(8), 3920; https://doi.org/10.3390/ijms26083920 - 21 Apr 2025

Abstract

The systemic treatment of breast cancer has evolved remarkably over the past decades. With the introduction of immune checkpoint inhibitors (ICIs), clinical outcomes for solid tumor malignancies have significantly improved. However, in breast cancer, the indication for ICIs is currently limited to triple-negative [...] Read more.

The systemic treatment of breast cancer has evolved remarkably over the past decades. With the introduction of immune checkpoint inhibitors (ICIs), clinical outcomes for solid tumor malignancies have significantly improved. However, in breast cancer, the indication for ICIs is currently limited to triple-negative breast cancer (TNBC) only. In high-risk luminal B hormone receptor-positive (HR+) breast cancer (BC) and HER2-positive (HER2+) BC, modest efficacy of ICI and chemotherapy combinations were identified in the neoadjuvant setting. To address the unmet need, several novel immunotherapy strategies are being tested in ongoing clinical trials as summarized in the current review: bispecific antibodies, chimeric antigen receptor T-cell therapy (CAR-T), T-cell receptors (TCRs), tumor-infiltrating lymphocytes (TILs), tumor vaccines, and oncolytic virus therapy. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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27 pages, 2958 KiB

Open AccessReview

Tumor Microenvironment Dynamics of Triple-Negative Breast Cancer Under Radiation Therapy

by Suryakant Niture, Subhajit Ghosh, Jerry Jaboin and Danushka Seneviratne

Int. J. Mol. Sci. 2025, 26(6), 2795; https://doi.org/10.3390/ijms26062795 - 20 Mar 2025

Viewed by 649

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10–15% of initial breast cancer diagnosis, due to its [...] Read more.

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of estrogen receptors (ER), progesterone receptors (PR), and HER2 expression. While TNBC is relatively less common, accounting for only 10–15% of initial breast cancer diagnosis, due to its aggressive nature, it carries a worse prognosis in comparison to its hormone receptor-positive counterparts. Despite significant advancements in the screening, diagnosis, and treatment of breast cancer, TNBC remains an important public health burden. Following treatment with chemotherapy, surgery, and radiation, over 40% of TNBC patients experience relapse within 3 years and achieve the least benefit from post-mastectomy radiation. The tumor microenvironment environment (TME) is pivotal in TNBC initiation, progression, immune evasion, treatment resistance, and tumor prognosis. TME is a complex network that consists of immune cells, non-immune cells, and soluble factors located in the region adjacent to the tumor that modulates the therapeutic response differentially between hormone receptor-positive breast cancer and TNBC. While the mechanisms underlying the radiation resistance of TNBC remain unclear, the immunosuppressive TME of TNBC has been implicated in chemotherapeutic resistance. Radiation therapy (RT) is known to alter the TME; however, immune changes elicited by radiation are poorly characterized to date, and whether these immune changes contribute to radiation resistance remains unknown. This review delves into the distinct characteristics of the TNBC TME, explores how RT influences TME dynamics, and examines mechanisms underlying tumor radiosensitization, radioresistance, and immune responses. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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14 pages, 1388 KiB

Open AccessReview

The Role of Molecular Profiling in De-Escalation of Toxic Therapy in Breast Cancer

by Sonia Y. Khan, Tonjeh Bah and Rakhshanda Layeequr Rahman

Int. J. Mol. Sci. 2025, 26(3), 1332; https://doi.org/10.3390/ijms26031332 - 4 Feb 2025

Viewed by 893

Abstract

The prevalence and mortality associated with breast cancer have forced healthcare providers to leverage surgery, chemotherapy, radiation therapy, and immunotherapy to achieve a cure. Whereas mortality has significantly dropped over the decades, long-term toxicities and healthcare costs are prohibitive. Therefore, a better understanding [...] Read more.

The prevalence and mortality associated with breast cancer have forced healthcare providers to leverage surgery, chemotherapy, radiation therapy, and immunotherapy to achieve a cure. Whereas mortality has significantly dropped over the decades, long-term toxicities and healthcare costs are prohibitive. Therefore, a better understanding of tumor biology through molecular profiling is being utilized for de-escalation of treatment where appropriate. As research evolves, there is growing evidence that less aggressive treatment regimens, when appropriately tailored, can be equally effective for certain patient populations. This approach not only enhances the quality of life for patients by reducing the financial, physical, and emotional burdens associated with more invasive therapies but also promotes a more personalized treatment strategy. By focusing on precision medicine and understanding the biological characteristics of tumors, healthcare providers and patients can make informed decisions that balance safety with efficacy. The field of molecular profiling is a promising avenue for precision-targeted de-escalation and escalation of therapy to minimize the risk–benefit ratio. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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13 pages, 880 KiB

Open AccessReview

CDK4/6 Inhibitor Resistance in Hormone Receptor-Positive Metastatic Breast Cancer: Translational Research, Clinical Trials, and Future Directions

by Jin Sun Lee, Hannah Hackbart, Xiaojiang Cui and Yuan Yuan

Int. J. Mol. Sci. 2023, 24(14), 11791; https://doi.org/10.3390/ijms241411791 - 22 Jul 2023

Cited by 14 | Viewed by 5005

Abstract

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains [...] Read more.

The emergence of CDK4/6 inhibitors, such as palbociclib, ribociclib, and abemaciclib, has revolutionized the treatment landscape for hormone receptor-positive breast cancer. These agents have demonstrated significant clinical benefits in terms of both progression-free survival and overall survival. However, resistance to CDK4/6 inhibitors remains a challenge, limiting their long-term efficacy. Understanding the complex mechanisms driving resistance is crucial for the development of novel therapeutic strategies and the improvement of patient outcomes. Translational research efforts, such as preclinical models and biomarker studies, offer valuable insight into resistance mechanisms and may guide the identification of novel combination therapies. This review paper aims to outline the reported mechanisms underlying CDK4/6 inhibitor resistance, drawing insights from both clinical data and translational research in order to help direct the future of treatment for hormone receptor-positive metastatic breast cancer. Full article

(This article belongs to the Special Issue Breast Cancers: From Molecular Basis to Therapy)

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