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16 pages, 3342 KiB

Open AccessArticle

Prognostic Value of SGK1 and Bcl-2 in Invasive Breast Cancer

by Umaima Al-Alem, Garth H. Rauscher, Qais Al Alem, Andre Kajdacsy-Balla and Abeer M. Mahmoud

Cancers 2023, 15(12), 3151; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15123151 - 11 Jun 2023

Cited by 3 | Viewed by 1348

It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the [...] Read more.

It is crucial to understand molecular alterations in breast cancer and how they relate to clinicopathologic factors. We have previously shown that the glucocorticoid receptor (GCR) protein expression was reduced in invasive breast carcinoma compared to normal breast tissue. Glucocorticoids, signaling through the GCR, regulate several cellular processes via downstream targets such as serum/glucocorticoid-regulated kinase 1 (SGK1) and B-cell lymphoma 2 (Bcl-2). We measured the expression of SGK1 and Bcl-2, in respective breast cancer tissue arrays, from a multiracial cohort of breast cancer patients. Higher cytoplasmic SGK1 staining was stronger in breast cancer tissue compared to normal tissue, especially in hormone receptor-negative cases. Conversely, the expression of cytoplasmic Bcl-2 was reduced in breast cancer compared to normal tissue, especially in hormone receptor-negative cases. Bcl-2 staining was associated with the self-reported racial/ethnic category, an earlier clinical stage, a lower histological grade, and a higher survival rate. Bcl-2 expression was associated with longer survival in models adjusted for age and race (HR = 0.32, 95% CI: 0.15, 0.65), and Bcl-2 expression remained strongly positively associated with protection from breast cancer death, with additional adjustments for ER/PR status (HR = 0.41, 95% CI: 0.2, 0.85). SGK1 and Bcl-2 may play biological roles in breast cancer development and/or progression. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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15 pages, 2601 KiB

Open AccessArticle

Cancer Cells Upregulate Tau to Gain Resistance to DNA Damaging Agents

by Thomas Rico, Marine Denechaud, Raphaelle Caillierez, Thomas Comptdaer, Eric Adriaenssens, Luc Buée and Bruno Lefebvre

Cancers 2023, 15(1), 116; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers15010116 - 24 Dec 2022

Cited by 2 | Viewed by 1918

Abstract

Recent reports suggested a role for microtubules in double-strand-DNA break repair. We herein investigated the role of the microtubule-associated protein Tau in radio- and chemotherapy. Noticeably, a lowered expression of Tau in breast cancer cell lines resulted in a significant decrease in mouse-xenograft [...] Read more.

Recent reports suggested a role for microtubules in double-strand-DNA break repair. We herein investigated the role of the microtubule-associated protein Tau in radio- and chemotherapy. Noticeably, a lowered expression of Tau in breast cancer cell lines resulted in a significant decrease in mouse-xenograft breast tumor volume after doxorubicin or X-ray treatments. Furthermore, the knockdown of Tau impaired the classical nonhomologous end-joining pathway and led to an improved cellular response to both bleomycin and X-rays. Investigating the mechanism of Tau’s protective effect, we found that one of the main mediators of response to double-stranded breaks in DNA, the tumor suppressor p53-binding protein 1 (53BP1), is sequestered in the cytoplasm as a consequence of Tau downregulation. We demonstrated that Tau allows 53BP1 to translocate to the nucleus in response to DNA damage by chaperoning microtubule protein trafficking. Moreover, Tau knockdown chemo-sensitized cancer cells to drugs forming DNA adducts, such as cisplatin and oxaliplatin, and further suggested a general role of Tau in regulating the nuclear trafficking of DNA repair proteins. Altogether, these results suggest that Tau expression in cancer cells may be of interest as a molecular marker for response to DNA-damaging anti-cancer agents. Clinically targeting Tau could sensitize tumors to DNA-damaging treatments. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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10 pages, 395 KiB

Open AccessArticle

Prognostic Potential of Immune Inflammatory Biomarkers in Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

by Marta Truffi, Federico Sottotetti, Nadav Gafni, Sara Albasini, Francesca Piccotti, Carlo Morasso, Valentina Tibollo, Michela Mocchi, Valentina Zanella and Fabio Corsi

Cancers 2022, 14(21), 5287; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215287 - 27 Oct 2022

Cited by 7 | Viewed by 1531

Abstract

Immune inflammatory biomarkers are easily obtained and inexpensive blood-based parameters that recently showed prognostic and predictive value in many solid tumors. In this study, we aimed to investigate the role of these biomarkers in predicting distant relapse in breast cancer patients treated with [...] Read more.

Immune inflammatory biomarkers are easily obtained and inexpensive blood-based parameters that recently showed prognostic and predictive value in many solid tumors. In this study, we aimed to investigate the role of these biomarkers in predicting distant relapse in breast cancer patients treated with neoadjuvant chemotherapy (NACT). All breast cancer patients who referred to our Breast Unit and underwent NACT were retrospectively reviewed. The pre-treatment neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR), and pan-immune-inflammation value (PIV) were calculated from complete blood counts. The primary outcome was 5-year distant-metastasis-free survival (DMFS). In receiver operating characteristic analyses, the optimal cutoff values for the NLR, PLR, MLR, and PIV were determined at 2.25, 152.46, 0.25, and 438.68, respectively. High levels of the MLR, but not the NLR, PLR, or PIV, were associated with improved 5-year DMSF in the study population using both univariate (HR 0.52, p = 0.03) and multivariate analyses (HR, 0.44; p = 0.02). Our study showed that the MLR was a significant independent parameter affecting DMFS in breast cancer patients undergoing NACT. Prospective studies are required to confirm this finding and to define reliable cutoff values, thus leading the way for the clinical application of this biomarker. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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21 pages, 3611 KiB

Open AccessArticle

Novel BH4-BCL-2 Domain Antagonists Induce BCL-2-Mediated Apoptosis in Triple-Negative Breast Cancer

by Vishnupriya Kanakaveti, Sakthivel Ramasamy, Rahul Kanumuri, Vaishnavi Balasubramanian, Roshni Saravanan, Inemai Ezhil, Ravishankar Pitani, Ganesh Venkatraman, Suresh Kumar Rayala and M. Michael Gromiha

Cancers 2022, 14(21), 5241; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14215241 - 26 Oct 2022

Cited by 1 | Viewed by 2071

Abstract

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical [...] Read more.

Targeting the challenging tumors lacking explicit markers and predictors for chemosensitivity is one of the major impediments of the current cancer armamentarium. Triple-negative breast cancer (TNBC) is an aggressive and challenging molecular subtype of breast cancer, which needs astute strategies to achieve clinical success. The pro-survival B-cell lymphoma 2 (BCL-2) overexpression reported in TNBC plays a central role in deterring apoptosis and is a promising target. Here, we propose three novel BH4 mimetic small molecules, SM396, a covalent binder, and two non-covalent binders, i.e., SM216 and SM949, which show high binding affinity (nM) and selectivity, designed by remodeling the existing BCL-2 chemical space. Our mechanistic studies validate the selectivity of the compounds towards cancerous cells and not on normal cells. A series of functional assays illustrated BCL-2-mediated apoptosis in the tumor cells as a potent anti-cancerous mechanism. Moreover, the compounds exhibited efficacious in vivo activity as single agents in the MDA-MB-231 xenograft model (at nanomolar dosage). Overall, these findings depict SM216, SM396, and SM949 as promising leads, pointing to the clinical translation of these compounds in targeting triple-negative breast cancer. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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15 pages, 1506 KiB

Open AccessArticle

Comparison of Genomic Profiling Data with Clinical Parameters: Implications for Breast Cancer Prognosis

by José A. López-Ruiz, Jon A. Mieza, Ignacio Zabalza and María d. M. Vivanco

Cancers 2022, 14(17), 4197; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14174197 - 30 Aug 2022

Cited by 3 | Viewed by 1402

Abstract

Precise prognosis is crucial for selection of adjuvant therapy in breast cancer. Molecular subtyping is increasingly used to complement immunohistochemical and pathological classification and to predict recurrence. This study compares both outcomes in a clinical setting. Molecular subtyping (MammaPrint^®, TargetPrint^® [...] Read more.

Precise prognosis is crucial for selection of adjuvant therapy in breast cancer. Molecular subtyping is increasingly used to complement immunohistochemical and pathological classification and to predict recurrence. This study compares both outcomes in a clinical setting. Molecular subtyping (MammaPrint^®, TargetPrint^®, and BluePrint^®) and pathological classification data were compared in a cohort of 143 breast cancer patients. High risk clinical factors were defined by a value of the proliferation factor Ki67 equal or higher than 14% and/or high histological grade. The results from molecular classification were considered as reference. Core needle biopsies were found to be comparable to surgery samples for molecular classification. Discrepancies were found between molecular and pathological subtyping of the samples, including misclassification of HER2-positive tumors and the identification of a significant percentage of genomic high risk T1N0 tumors. In addition, 20% of clinical low-risk tumors showed genomic high risk, while clinical high-risk samples included 42% of cases with genomic low risk. According to pathological subtyping, a considerable number of breast cancer patients would not receive the appropriate systemic therapy. Our findings support the need to determine the molecular subtype of invasive breast tumors to improve breast cancer management. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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19 pages, 3378 KiB

Open AccessArticle

NRG1/ERBB3/ERBB2 Axis Triggers Anchorage-Independent Growth of Basal-like/Triple-Negative Breast Cancer Cells

by Carmen Miano, Alessandra Morselli, Francesca Pontis, Chiara Bongiovanni, Francesca Sacchi, Silvia Da Pra, Donatella Romaniello, Riccardo Tassinari, Michela Sgarzi, Elvira Pantano, Carlo Ventura, Mattia Lauriola and Gabriele D’Uva

Cancers 2022, 14(7), 1603; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14071603 - 22 Mar 2022

Cited by 5 | Viewed by 3309

Abstract

ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast [...] Read more.

ERBB3, also known as HER3, is a tyrosine kinase transmembrane receptor of the ERBB family. Upon binding to neuregulin 1 (NRG1), ERBB3 preferentially dimerizes with HER2 (ERBB2), in turn inducing aggressive features in several cancer types. The analysis of a dataset of breast cancer patients unveiled that higher ERBB3 mRNA expression correlates with shorter relapse-free survival in basal-like breast cancers, despite low ERBB3 expression in this breast cancer subtype. Administration of neuregulin 1 beta (NRG1β) significantly affected neither cellular proliferation nor the basal migratory ability of basal-like/triple-negative quasi-normal MCF10A breast cells, cultured in mono-layer conditions. Furthermore, no significant regulation in cell morphology or in the expression of basal/myoepithelial and luminal markers was observed upon stimulation with NRG1β. In non-adherent conditions, NRG1β administration to MCF10A cells did not significantly influence cell survival; however, it robustly induced cell growth as spheroids (3D growth). Intriguingly, a remarkable upregulation of ERBB3 and ERBB2 protein abundance was observed in 3D compared to 2D cell cultures, and NRG1β-induced 3D cell growth was efficiently prevented by the anti-HER2 monoclonal antibody pertuzumab. Similar results were obtained by the analysis of basal-like/triple-negative breast cancer cellular models, MDA-MB-468 and MDA-MB-231 cells, in which NRG1β induced anchorage-independent cell growth that in turn was prevented or reduced by the simultaneous administration of anti-HER2 neutralizing antibodies. Finally, the ability of pertuzumab in suppressing NRG1β-induced 3D growth was also evaluated and confirmed in MCF10A engineered with HER2-overexpression. We suggest that the NRG1/ERBB3/ERBB2 pathway promotes the anchorage-independent growth of basal-like breast cancer cells. Importantly, we provide evidence that ERBB2 neutralization, in particular by pertuzumab, robustly inhibits this process. Our results pave the way towards the development of novel anticancer strategies for basal-like breast cancer patients based on the interception of the NRG1/ERBB3/ERBB2 signaling axis. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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23 pages, 1830 KiB

Open AccessArticle

Human Cytomegalovirus Seropositivity and Viral DNA in Breast Tumors Are Associated with Poor Patient Prognosis

by Zelei Yang, Xiaoyun Tang, Maria Eloisa Hasing, Xiaoli Pang, Sunita Ghosh, Todd P. W. McMullen, David N. Brindley and Denise G. Hemmings

Cancers 2022, 14(5), 1148; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14051148 - 23 Feb 2022

Cited by 5 | Viewed by 2011

Abstract

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. Detection of HCMV DNA and/or proteins in breast tumors varies considerably, ranging from 0–100%. In this study, nested PCR to detect HCMV glycoprotein B (gB) DNA in breast tumors was shown to be [...] Read more.

Human cytomegalovirus (HCMV) infects 40–70% of adults in developed countries. Detection of HCMV DNA and/or proteins in breast tumors varies considerably, ranging from 0–100%. In this study, nested PCR to detect HCMV glycoprotein B (gB) DNA in breast tumors was shown to be sensitive and specific in contrast to the detection of DNA for immediate early genes. HCMV gB DNA was detected in 18.4% of 136 breast tumors while 62.8% of 94 breast cancer patients were seropositive for HCMV. mRNA for the HCMV immediate early gene was not detected in any sample, suggesting viral latency in breast tumors. HCMV seropositivity was positively correlated with age, body mass index and menopause. Patients who were HCMV seropositive or had HCMV DNA in their tumors were 5.61 (CI 1.77–15.67, p = 0.003) or 5.27 (CI 1.09–28.75, p = 0.039) times more likely to develop Stage IV metastatic tumors, respectively. Patients with HCMV DNA in tumors experienced reduced relapse-free survival (p = 0.042). Being both seropositive with HCMV DNA-positive tumors was associated with vascular involvement and metastasis. We conclude that determining the seropositivity for HCMV and detection of HCMV gB DNA in the breast tumors could identify breast cancer patients more likely to develop metastatic cancer and warrant special treatment. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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Review

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17 pages, 596 KiB

Open AccessEditor’s ChoiceReview

Programmed Death-Ligand 1 (PD-L1) as Immunotherapy Biomarker in Breast Cancer

by Martín Núñez Abad, Silvia Calabuig-Fariñas, Miriam Lobo de Mena, Susana Torres-Martínez, Clara García González, José Ángel García García, Vega Iranzo González-Cruz and Carlos Camps Herrero

Cancers 2022, 14(2), 307; https://0-doi-org.brum.beds.ac.uk/10.3390/cancers14020307 - 08 Jan 2022

Cited by 18 | Viewed by 5635

Abstract

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation [...] Read more.

Breast cancer constitutes the most common malignant neoplasm in women around the world. Approximately 12% of patients are diagnosed with metastatic stage, and between 5 and 30% of early or locally advanced BC patients will relapse, making it an incurable disease. PD-L1 ligation is an immune inhibitory molecule of the activation of T cells, playing a relevant role in numerous types of malignant tumors, including BC. The objective of the present review is to analyze the role of PD-L1 as a biomarker in the different BC subtypes, adding clinical trials with immune checkpoint inhibitors and their applicable results. Diverse trials using immunotherapy with anti-PD-1/PD-L1 in BC, as well as prospective or retrospective cohort studies about PD-L1 in BC, were included. Despite divergent results in the reviewed studies, PD-L1 seems to be correlated with worse prognosis in the hormone receptor positive subtype. Immune checkpoints inhibitors targeting the PD-1/PD-L1 axis have achieved great response rates in TNBC patients, especially in combination with chemotherapy, making immunotherapy a new treatment option in this scenario. However, the utility of PD-L1 as a predictive biomarker in the rest of BC subtypes remains unclear. In addition, predictive differences have been found in response to immunotherapy depending on the stage of the tumor disease. Therefore, a better understanding of tumor microenvironment, as well as identifying new potential biomarkers or combined index scores, is necessary in order to make a better selection of the subgroups of BC patients who will derive benefit from immune checkpoint inhibitors. Full article

(This article belongs to the Special Issue Advances in Breast Cancer Research: From Biology to Pathology)

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