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10 pages, 1629 KiB

Open AccessArticle

Contrast-Enhanced Mammography (CEM) Capability to Distinguish Molecular Breast Cancer Subtypes

by Elzbieta Luczynska, Tomasz Piegza, Joanna Szpor, Sylwia Heinze, Tadeusz Popiela, Jaromir Kargol and Wojciech Rudnicki

Biomedicines 2022, 10(10), 2384; https://doi.org/10.3390/biomedicines10102384 - 24 Sep 2022

Cited by 11 | Viewed by 3111

Abstract

With breast cancer ranking first among the most common malignant neoplasms in the world, new techniques of early detection are in even more demand than before. Our awareness of tumors’ biology is expanding and may be used to treat patients more efficiently. A [...] Read more.

With breast cancer ranking first among the most common malignant neoplasms in the world, new techniques of early detection are in even more demand than before. Our awareness of tumors’ biology is expanding and may be used to treat patients more efficiently. A link between radiology and pathology was searched for in our study, as well as the answer to the question of whether a tumor type can be seen on contrast-enhanced mammography and if such knowledge may serve as part of precision medicine. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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31 pages, 8043 KiB

Open AccessArticle

A Drug Screening Reveals Minocycline Hydrochloride as a Therapeutic Option to Prevent Breast Cancer Cells Extravasation across the Blood–Brain Barrier

by Joana Godinho-Pereira, Margarida Dionísio Lopes, Ana Rita Garcia, Hugo M. Botelho, Rui Malhó, Inês Figueira and Maria Alexandra Brito

Biomedicines 2022, 10(8), 1988; https://doi.org/10.3390/biomedicines10081988 - 16 Aug 2022

Cited by 7 | Viewed by 3579

Abstract

Among breast cancer (BC) patients, 15–25% develop BC brain metastases (BCBM), a severe condition due to the limited therapeutic options, which points to the need for preventive strategies. We aimed to find a drug able to boost blood–brain barrier (BBB) properties and prevent [...] Read more.

Among breast cancer (BC) patients, 15–25% develop BC brain metastases (BCBM), a severe condition due to the limited therapeutic options, which points to the need for preventive strategies. We aimed to find a drug able to boost blood–brain barrier (BBB) properties and prevent BC cells (BCCs) extravasation, among PI3K, HSP90, and EGFR inhibitors and approved drugs. We used BCCs (4T1) and BBB endothelial cells (b.End5) to identify molecules with toxicity to 4T1 cells and safe for b.End5 cells. Moreover, we used those cells in mixed cultures to perform a high-throughput microscopy screening of drugs’ ability to ameliorate BBB properties and prevent BCCs adhesion and migration across the endothelium, as well as to analyse miRNAs expression and release profiles. KW-2478, buparlisib, and minocycline hydrochloride (MH) promoted maximal expression of the junctional protein β-catenin and induced 4T1 cells nucleus changes. Buparlisib and MH further decreased 4T1 adhesion. MH was the most promising in preventing 4T1 migration and BBB disruption, tumour and endothelial cytoskeleton-associated proteins modifications, and miRNA deregulation. Our data revealed MH’s ability to improve BBB properties, while compromising BCCs viability and interaction with BBB endothelial cells, besides restoring miRNAs’ homeostasis, paving the way for MH repurposing for BCBM prevention. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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23 pages, 4642 KiB

Open AccessArticle

High Levels of Progesterone Receptor B in MCF-7 Cells Enable Radical Anti-Tumoral and Anti-Estrogenic Effect of Progestin

by Natasa Bajalovic, Yu Zuan Or, Amanda R. E. Woo, Shi Hao Lee and Valerie C. L. Lin

Biomedicines 2022, 10(8), 1860; https://doi.org/10.3390/biomedicines10081860 - 2 Aug 2022

Cited by 7 | Viewed by 2800

Abstract

The widely reported conflicting effects of progestin on breast cancer suggest that the progesterone receptor (PR) has dual functions depending on the cellular context. Cell models that enable PR to fully express anti-tumoral properties are valuable for the understanding of molecular determinant(s) of [...] Read more.

The widely reported conflicting effects of progestin on breast cancer suggest that the progesterone receptor (PR) has dual functions depending on the cellular context. Cell models that enable PR to fully express anti-tumoral properties are valuable for the understanding of molecular determinant(s) of the anti-tumoral property. This study evaluated whether the expression of high levels of PR in MCF-7 cells enabled a strong anti-tumoral response to progestin. MCF-7 cells were engineered to overexpress PRB by stable transfection. A single dose of Promegestone (R5020) induced an irreversible cell growth arrest and senescence-associated secretory phenotype in MCF-7 cells with PRB overexpression (MCF-7PRB cells) but had no effect on MCF-7 cells with PRA overexpression. The growth-arresting effect was associated with downregulations of cyclin A2 and B1, CDK2, and CDK4 despite an initial upregulation of cyclin A2 and B1. R5020 also induced an evident activation of Nuclear Factor κB (NF-κB) and upregulation of interleukins IL-1α, IL-1β, and IL-8. Although R5020 caused a significant increase of CD24+CD44+ cell population, R5020-treated MCF-7PRB cells were unable to form tumorspheres and underwent massive apoptosis, which is paradoxically associated with marked downregulations of the pro-apoptotic proteins BID, BAX, PARP, and Caspases 7 and 8, as well as diminution of anti-apoptotic protein BCL-2. Importantly, R5020-activated PRB abolished the effect of estrogen. This intense anti-estrogenic effect was mediated by marked downregulation of ERα and pioneer factor FOXA1, leading to diminished chromatin-associated ERα and FOXA1 and estrogen-induced target gene expression. In conclusion, high levels of agonist-activated PRB in breast cancer cells can be strongly anti-tumoral and anti-estrogenic despite the initial unproductive cell cycle acceleration. Repression of ERα and FOXA1 expression is a major mechanism for the strong anti-estrogenic effect. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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17 pages, 7787 KiB

Open AccessArticle

In Vivo Validation of Diffuse Optical Imaging with a Dual-Direction Measuring Module of Parallel-Plate Architecture for Breast Tumor Detection

by Jhao-Ming Yu, Liang-Yu Chen, Min-Cheng Pan, Ya-Fen Hsu, Min-Chun Pan, Yi-Ling Lin, Sheng-Yih Sun and Chia-Cheng Chou

Biomedicines 2022, 10(5), 1040; https://doi.org/10.3390/biomedicines10051040 - 30 Apr 2022

Cited by 2 | Viewed by 1957

Abstract

We demonstrate a working prototype of an optical breast imaging system involving parallel-plate architecture and a dual-direction scanning scheme designed in combination with a mammography machine; this system was validated in a pilot study to demonstrate its application in imaging healthy and malignant [...] Read more.

We demonstrate a working prototype of an optical breast imaging system involving parallel-plate architecture and a dual-direction scanning scheme designed in combination with a mammography machine; this system was validated in a pilot study to demonstrate its application in imaging healthy and malignant breasts in a clinical environment. The components and modules of the self-developed imaging system are demonstrated and explained, including its measuring architecture, scanning mechanism, and system calibration, and the reconstruction algorithm is presented. Additionally, the evaluation of feature indices that succinctly demonstrate the corresponding transmission measurements may provide insight into the existence of malignant tissue. Moreover, five cases are presented including one subject without disease (a control measure), one benign case, one suspected case, one invasive ductal carcinoma, and one positive case without follow-up treatment. A region-of-interest analysis demonstrated significant differences in absorption between healthy and malignant breasts, revealing the average contrast between the abnormalities and background tissue to exceed 1.4. Except for ringing artifacts, the average scattering property of the structure densities was 0.65–0.85 mm⁻¹. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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14 pages, 792 KiB

Open AccessArticle

Whole-Exome Sequencing of Germline Variants in Non-BRCA Families with Hereditary Breast Cancer

by Yaxuan Liu, Hafdis T. Helgadottir, Pedram Kharaziha, Jungmin Choi, Francesc López-Giráldez, Shrikant M. Mane, Veronica Höiom, Carl Christofer Juhlin, Catharina Larsson and Svetlana Bajalica-Lagercrantz

Biomedicines 2022, 10(5), 1004; https://doi.org/10.3390/biomedicines10051004 - 26 Apr 2022

Cited by 1 | Viewed by 3718

Abstract

Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of [...] Read more.

Breast cancer is the most prevalent malignancy among women worldwide and hereditary breast cancer (HBC) accounts for about 5–10% of the cases. Today, the most recurrent genes known are BRCA1 and BRCA2, accounting for around 25% of familial cases. Although thousands of loss-of-function variants in more than twenty predisposing genes have been found, the majority of familial cases of HBC remain unexplained. The aim of this study was to identify new predisposing genes for HBC in three non-BRCA families with autosomal dominant inheritance pattern using whole-exome sequencing and functional prediction tools. No pathogenic variants in known hereditary cancer-related genes could explain the breast cancer susceptibility in these families. Among 2122 exonic variants with maximum minor allele frequency (MMAF) < 0.1%, between 17–35 variants with combined annotation-dependent depletion (CADD) > 20 segregated with disease in the three analyzed families. Selected candidate genes, i.e., UBASH3A, MYH13, UTP11L, and PAX7, were further evaluated using protein expression analysis but no alterations of cancer-related pathways were observed. In conclusion, identification of new high-risk cancer genes using whole-exome sequencing has been more challenging than initially anticipated, in spite of selected families with pronounced family history of breast cancer. A combination of low- and intermediate-genetic-risk variants may instead contribute the breast cancer susceptibility in these families. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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17 pages, 3241 KiB

Open AccessArticle

Prognostic Role of Androgen Receptor Expression in HER2+ Breast Carcinoma Subtypes

by Sandra Orrù, Emanuele Pascariello, Giovanni Sotgiu, Daniela Piras, Laura Saderi, Maria Rosaria Muroni, Ciriaco Carru, Caterina Arru, Cristina Mocci, Giampietro Pinna, Raffaele Barbara, Paolo Cossu-Rocca and Maria Rosaria De Miglio

Biomedicines 2022, 10(1), 164; https://doi.org/10.3390/biomedicines10010164 - 13 Jan 2022

Cited by 6 | Viewed by 2429

Abstract

HER2+ breast cancer (BC) is an aggressive subtype representing a genetically and biologically heterogeneous group of tumors resulting in variable prognosis and treatment response to HER2-targeted therapies according to estrogen (ER) and progesterone receptor (PR) expression. The relationship with androgen receptors (AR), a [...] Read more.

HER2+ breast cancer (BC) is an aggressive subtype representing a genetically and biologically heterogeneous group of tumors resulting in variable prognosis and treatment response to HER2-targeted therapies according to estrogen (ER) and progesterone receptor (PR) expression. The relationship with androgen receptors (AR), a member of the steroid hormone’s family, is unwell known in BC. The present study aims to evaluate the prognostic impact of AR expression in HER2+ BC subtypes. A total of 695 BCs were selected and reviewed, AR, ER, PR and HER2 expression in tumor cells were examined by immunohistochemical method, and the SISH method was used in case of HER2 with equivocal immunohistochemical score (2+). A high prevalence of AR expression (91.5%) in BC HER+ was observed, with minimal differences between luminal and non-luminal tumor. According to steroid receptor expression, tumors were classified in four subgroups, including BC luminal and non-luminal HER2+ expressing or not AR. The luminal BC HER2 + AR+ was associated with lower histological grade, lower tumor size, higher PR expression and lower HER2 intensity of expression (2+). Also, the non-luminal tumors AR+ showed lower tumor size and lower prognostic stage but frequently higher grade and higher HER2 intensity of expression (3+). These findings should suggest a different progression of luminal and non-luminal tumors, both expressing AR, and allow us to speculate that the molecular mechanisms of AR, involved in the biology of BC HER2 + AR+, differ in relation to ER and PR expression. Moreover, AR expression may be a useful predictor of prognosis for overall survival (OS) in HER2+ BC subtypes. Our findings suggest that AR expression evaluation in clinical practice could be utilized in clinical oncology to establish different aggressiveness in BC HER2+ subtypes. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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Review

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17 pages, 1025 KiB

Open AccessReview

Exploiting DNA Replication Stress as a Therapeutic Strategy for Breast Cancer

by Jing Zhang, Doug W. Chan and Shiaw-Yih Lin

Biomedicines 2022, 10(11), 2775; https://doi.org/10.3390/biomedicines10112775 - 1 Nov 2022

Cited by 6 | Viewed by 3624

Abstract

Proliferating cells rely on DNA replication to ensure accurate genome duplication. Cancer cells, including breast cancer cells, exhibit elevated replication stress (RS) due to the uncontrolled oncogenic activation, loss of key tumor suppressors, and defects in the DNA repair machinery. This intrinsic vulnerability [...] Read more.

Proliferating cells rely on DNA replication to ensure accurate genome duplication. Cancer cells, including breast cancer cells, exhibit elevated replication stress (RS) due to the uncontrolled oncogenic activation, loss of key tumor suppressors, and defects in the DNA repair machinery. This intrinsic vulnerability provides a great opportunity for therapeutic exploitation. An increasing number of drug candidates targeting RS in breast cancer are demonstrating promising efficacy in preclinical and early clinical trials. However, unresolved challenges lie in balancing the toxicity of these drugs while maintaining clinical efficacy. Furthermore, biomarkers of RS are urgently required to guide patient selection. In this review, we introduce the concept of targeting RS, detail the current therapies that target RS, and highlight the integration of RS with immunotherapies for breast cancer treatment. Additionally, we discuss the potential biomarkers to optimizing the efficacy of these therapies. Together, the continuous advances in our knowledge of targeting RS would benefit more patients with breast cancer. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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23 pages, 1163 KiB

Open AccessReview

Epigenetic Factors as Etiological Agents, Diagnostic Markers, and Therapeutic Targets for Luminal Breast Cancer

by Nguyen Xuan Thang, Seonho Yoo, Hyeonwoo La, Hyeonji Lee, Chanhyeok Park, Kyoung Sik Park and Kwonho Hong

Biomedicines 2022, 10(4), 748; https://doi.org/10.3390/biomedicines10040748 - 23 Mar 2022

Cited by 1 | Viewed by 3746

Abstract

Luminal breast cancer, an etiologically heterogeneous disease, is characterized by high steroid hormone receptor activity and aberrant gene expression profiles. Endocrine therapy and chemotherapy are promising therapeutic approaches to mitigate breast cancer proliferation and recurrence. However, the treatment of therapy-resistant breast cancer is [...] Read more.

Luminal breast cancer, an etiologically heterogeneous disease, is characterized by high steroid hormone receptor activity and aberrant gene expression profiles. Endocrine therapy and chemotherapy are promising therapeutic approaches to mitigate breast cancer proliferation and recurrence. However, the treatment of therapy-resistant breast cancer is a major challenge. Recent studies on breast cancer etiology have revealed the critical roles of epigenetic factors in luminal breast cancer tumorigenesis and drug resistance. Tumorigenic epigenetic factor-induced aberrant chromatin dynamics dysregulate the onset of gene expression and consequently promote tumorigenesis and metastasis. Epigenetic dysregulation, a type of somatic mutation, is a high-risk factor for breast cancer progression and therapy resistance. Therefore, epigenetic modulators alone or in combination with other therapies are potential therapeutic agents for breast cancer. Several clinical trials have analyzed the therapeutic efficacy of potential epi-drugs for breast cancer and reported beneficial clinical outcomes, including inhibition of tumor cell adhesion and invasiveness and mitigation of endocrine therapy resistance. This review focuses on recent findings on the mechanisms of epigenetic factors in the progression of luminal breast cancer. Additionally, recent findings on the potential of epigenetic factors as diagnostic biomarkers and therapeutic targets for breast cancer are discussed. Full article

(This article belongs to the Special Issue Breast Cancer: From Biology to Therapeutic Opportunities)

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