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Molecular Biology and Pathology of Breast Cancer

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (30 November 2018) | Viewed by 53524

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Prof. Dr. Martin Schreiber

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Guest Editor

Department of Obstetrics & Gynecology, Medical University of Vienna, 1090 Vienna, Austria
Interests: breast cancer; diagnostic and prognostic markers; gene expression; transcriptional regulation; genomics and transcriptomics; p53 pathway; hormone receptor pathways; epithelial-mesenchymal transition
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Molecular alterations are causal to the genesis and progression of cancer. It is widely predicted that the molecular profile of a tumor, more than traditional clinical and histopathological characteristics or even the tissue of origin, will ultimately determine the specific personalized therapy in the future. Many steps in this ongoing molecular revolution have been pioneered in breast cancer research and treatment. Arguably, the first molecularly targeted therapy plus companion diagnostics was clinically established for breast cancer decades ago: Tamoxifen for estrogen receptor positive, but not negative patients. Hereditary breast cancer has been a paradigm for genetic cancer susceptibility syndromes ever since the discovery of the breast cancer genes BRCA1 and BRCA2 more than twenty years ago. Molecular subtypes of breast cancer based on genome-wide expression profiling were reported as early as 2000, and are still widely-used in breast cancer research and prognosis.

Along these lines, this Special Issue welcomes submissions of research articles and reviews covering molecular aspects of the biology and pathology of breast cancer in humans and model organisms, including diagnostic, prognostic and predictive molecular biomarkers; molecularly targeted therapies; hereditary breast cancer and genes, mutations and polymorphisms with a role in breast cancer risk and biology; breast cancer genomics and transcriptomics; epigenetics and epigenomics of breast cancer.

Prof. Martin Schreiber
Guest Editor

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Keywords

Molecular mechanisms;
Diagnostic, prognostic and predictive molecular markers;
Current and novel immunohistochemical markers;
Molecular subtypes;
Molecularly targeted therapies;
Hereditary breast cancer;
Mutations and polymorphisms;
Breast cancer genomics and transcriptomics;
Epigenetics and epigenomics;
Preclinical models

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Published Papers (9 papers)

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Research

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21 pages, 2043 KiB

Open AccessArticle

Low-Frequency Mutational Heterogeneity of Invasive Ductal Carcinoma Subtypes: Information to Direct Precision Oncology

by Meagan B. Myers, Karen L. McKim, Malathi Banda, Nysia I. George and Barbara L. Parsons

Int. J. Mol. Sci. 2019, 20(5), 1011; https://doi.org/10.3390/ijms20051011 - 26 Feb 2019

Cited by 8 | Viewed by 2838

Abstract

Information regarding the role of low-frequency hotspot cancer-driver mutations (CDMs) in breast carcinogenesis and therapeutic response is limited. Using the sensitive and quantitative Allele-specific Competitor Blocker PCR (ACB-PCR) approach, mutant fractions (MFs) of six CDMs (PIK3CA H1047R and E545K, KRAS G12D and G12V, HRAS G12D, and BRAF V600E) were quantified in invasive ductal carcinomas (IDCs; including ~20 samples per subtype). Measurable levels (i.e., ≥ 1 × 10⁻⁵, the lowest ACB-PCR standard employed) of the PIK3CA H1047R, PIK3CA E545K, KRAS G12D, KRAS G12V, HRAS G12D, and BRAF V600E mutations were observed in 34/81 (42%), 29/81 (36%), 51/81 (63%), 9/81 (11%), 70/81 (86%), and 48/81 (59%) of IDCs, respectively. Correlation analysis using available clinicopathological information revealed that PIK3CA H1047R and BRAF V600E MFs correlate positively with maximum tumor dimension. Analysis of IDC subtypes revealed minor mutant subpopulations of critical genes in the MAP kinase pathway (KRAS, HRAS, and BRAF) were prevalent across IDC subtypes. Few triple-negative breast cancers (TNBCs) had appreciable levels of PIK3CA mutation, suggesting that individuals with TNBC may be less responsive to inhibitors of the PI3K/AKT/mTOR pathway. These results suggest that low-frequency hotspot CDMs contribute significantly to the intertumoral and intratumoral genetic heterogeneity of IDCs, which has the potential to impact precision oncology approaches. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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15 pages, 3170 KiB

Open AccessArticle

Association of the MDM2 SNP285 and SNP309 Genetic Variants with the Risk, Age at Onset and Prognosis of Breast Cancer in Central European Women: A Hospital-Based Case-Control Study

by Heidi Miedl, Jürgen Lebhard, Lisa Ehart and Martin Schreiber

Int. J. Mol. Sci. 2019, 20(3), 509; https://doi.org/10.3390/ijms20030509 - 25 Jan 2019

Cited by 10 | Viewed by 3728

Abstract

SNP309T>G (rs2279744) and SNP285G>C (rs117039649) in the MDM2 promoter are thought to have opposite effects on the binding of transcription factor SP1 (specificity protein 1), and consequently on MDM2 expression, p53 levels, cancer risk, age at onset, and prognosis. Here, we genotyped SNP309 and SNP285 in 406 Austrian breast cancer patients and 254 female controls. The SNP309GG genotype was associated with an increased breast cancer risk in p53 negative (OR, 1.82; 95% CI, 1.09–3.03; p = 0.02), but not p53 positive or unselected patients. In contrast, the SNP309TT genotype was associated with an earlier age at onset (TT, 57.0 ± 12.9; TG, 58.6 ± 13.9; GG, 59.7 ± 15.0 years; p = 0.048). 31% of SNP309TT, 26% of TG, and 13% of GG tumors were p53 positive (p = 0.034), indicating a lower selective pressure to mutate TP53 in the presence of the G-allele. Moreover, SNP309TT patients exhibited a shortened metastasis-free survival in multivariable analysis. Censoring carriers of the SNP285C-allele hardly altered the strength of these associations of SNP309, thus challenging the proposed antagonistic function of SNP285C towards SNP309G. The minor SNP285C-allele tended to be non-significantly associated with an increased breast cancer risk and a poor disease-free and metastasis-free survival, which may be bystander effects of its complete linkage disequilibrium with SNP309G. We conclude that the SNP309G-allele attenuates the p53-response and leads to a higher breast cancer risk, but also to a later onset of breast cancer and a trend towards a good prognosis. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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14 pages, 2023 KiB

Open AccessArticle

Prognostic Relevance of RIP140 and ERβ Expression in Unifocal Versus Multifocal Breast Cancers: A Preliminary Report

by Katharina Müller, Sophie Sixou, Christina Kuhn, Stephan Jalaguier, Doris Mayr, Nina Ditsch, Tobias Weissenbacher, Nadia Harbeck, Sven Mahner, Vincent Cavaillès and Udo Jeschke

Int. J. Mol. Sci. 2019, 20(2), 418; https://doi.org/10.3390/ijms20020418 - 18 Jan 2019

Cited by 7 | Viewed by 3986

Abstract

The aim of this study was to investigate the expression of two nuclear receptor transcriptional coregulators, namely RIP140 (receptor-interacting protein of 140 kDa) and LCoR (ligand-dependent corepressor) in unifocal versus multifocal breast cancers. The expression of these two proteins was analyzed by immunohistochemistry in a matched-pair cohort of 21 unifocal and 21 multifocal breast tumors. The expression of the two estrogen receptors (ERα and ERβ) was studied in parallel. RIP140 and LCoR levels appeared lower in unifocal tumors compared to multifocal samples (decreased of immune-reactive scores and reduced number of high expressing cells). In both tumor types, RIP140 and LCoR expression was correlated with each other and with expression of ERβ. Very interestingly, the expression of RIP140, LCoR, and ERβ was inversely correlated with overall survival only for the unifocal group. The negative correlation with overall and recurrence free survival was more pronounced in patients whose unifocal tumors expressed high levels of both RIP140 and ERβ. Altogether, this preliminary report indicates that the ERβ/RIP140 signaling is altered in unifocal breast cancers and correlated with patient outcome. Further investigation is needed to decipher the molecular mechanisms and the biological relevance of this deregulation. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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18 pages, 2463 KiB

Open AccessArticle

Inhibition of Breast Cancer Cell Invasion by Ras Suppressor-1 (RSU-1) Silencing Is Reversed by Growth Differentiation Factor-15 (GDF-15)

by Vasiliki Gkretsi, Maria Louca, Andreas Stylianou, George Minadakis, George M. Spyrou and Triantafyllos Stylianopoulos

Int. J. Mol. Sci. 2019, 20(1), 163; https://doi.org/10.3390/ijms20010163 - 4 Jan 2019

Cited by 21 | Viewed by 4693

Abstract

Extracellular matrix (ECM)-related adhesion proteins are important in metastasis. Ras suppressor-1 (RSU-1), a suppressor of Ras-transformation, is localized to cell–ECM adhesions where it interacts with the Particularly Interesting New Cysteine-Histidine rich protein (PINCH-1), being connected to Integrin Linked Kinase (ILK) and alpha-parvin (PARVA), a direct actin-binding protein. RSU-1 was also found upregulated in metastatic breast cancer (BC) samples and was recently demonstrated to have metastasis-promoting properties. In the present study, we transiently silenced RSU-1 in BC cells, MCF-7 and MDA-MB-231. We found that RSU-1 silencing leads to downregulation of Growth Differentiation Factor-15 (GDF-15), which has been associated with both actin cytoskeleton reorganization and metastasis. RSU-1 silencing also reduced the mRNA expression of PINCH-1 and cell division control protein-42 (Cdc42), while increasing that of ILK and Rac regardless of the presence of GDF-15. However, the downregulation of actin-modulating genes PARVA, RhoA, Rho associated kinase-1 (ROCK-1), and Fascin-1 following RSU-1 depletion was completely reversed by GDF-15 treatment in both cell lines. Moreover, complete rescue of the inhibitory effect of RSU-1 silencing on cell invasion was achieved by GDF-15 treatment, which also correlated with matrix metalloproteinase-2 expression. Finally, using a graph clustering approach, we corroborated our findings. This is the first study providing evidence of a functional association between RSU-1 and GDF-15 with regard to cancer cell invasion. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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12 pages, 2268 KiB

Open AccessCommunication

HER2 Heterogeneity Is Associated with Poor Survival in HER2-Positive Breast Cancer

by Mari Hosonaga, Yoshimi Arima, Oltea Sampetrean, Daisuke Komura, Ikuko Koya, Takashi Sasaki, Eiichi Sato, Hideyuki Okano, Jun Kudoh, Shumpei Ishikawa, Hideyuki Saya and Takashi Ishikawa

Int. J. Mol. Sci. 2018, 19(8), 2158; https://doi.org/10.3390/ijms19082158 - 24 Jul 2018

Cited by 25 | Viewed by 5164

Abstract

Intratumoral human epidermal growth factor receptor 2 (HER2) heterogeneity has been reported in 16–36% of HER2-positive breast cancer and its clinical impact is under discussion. We examined the biological effects of HER2-heterogeneity on mouse models and analyzed metastatic brains by RNA sequence analysis. A metastatic mouse model was developed using 231-Luc (triple negative cells) and 2 HER2-positive cell lines, namely, HER2-60 and HER2-90 which showed heterogeneous and monotonous HER2 expressions, respectively. Metastatic lesions developed in 3 weeks in all the mice injected with HER2-60 cells, and in 69% of the mice injected with HER2-90 and 87.5% of the mice injected with 231-Luc. The median survival days of mice injected with 231-Luc, HER2-60, and HER2-90 cells were 29 (n = 24), 24 (n = 22) and 30 (n = 13) days, respectively. RNA sequence analysis showed that CASP-1 and its related genes were significantly downregulated in metastatic brain tumors with HER2-60 cells. The low expression of caspase-1 could be a new prognostic biomarker for early relapse in HER2-positive breast cancer. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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Review

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13 pages, 978 KiB

Open AccessReview

The Cytoskeletal Protein Cyclase-Associated Protein 1 (CAP1) in Breast Cancer: Context-Dependent Roles in Both the Invasiveness and Proliferation of Cancer Cells and Underlying Cell Signals

by Rokib Hasan and Guo-Lei Zhou

Int. J. Mol. Sci. 2019, 20(11), 2653; https://doi.org/10.3390/ijms20112653 - 30 May 2019

Cited by 15 | Viewed by 5152

Abstract

As a conserved actin-regulating protein, CAP (adenylyl Cyclase-Associated Protein) functions to facilitate the rearrangement of the actin cytoskeleton. The ubiquitously expressed isoform CAP1 drives mammalian cell migration, and accordingly, most studies on the involvement of CAP1 in human cancers have largely been based on the rationale that up-regulated CAP1 will stimulate cancer cell migration and invasiveness. While findings from some studies reported so far support this case, lines of evidence largely from our recent studies point to a more complex and profound role for CAP1 in the invasiveness of cancer cells, where the potential activation of cell adhesion signaling is believed to play a key role. Moreover, CAP1 was also found to control proliferation in breast cancer cells, through the regulation of ERK (External signal-Regulated Kinase). Alterations in the activities of FAK (Focal Adhesion Kinase) and ERK from CAP1 depletion that are consistent to the opposite adhesion and proliferation phenotypes were detected in the metastatic and non-metastatic breast cancer cells. In this review, we begin with the overview of the literature on CAP, by highlighting the molecular functions of mammalian CAP1 in regulating the actin cytoskeleton and cell adhesion. We will next discuss the role of the FAK/ERK axis, and possibly Rap1, in mediating CAP1 signals to control breast cancer cell adhesion, invasiveness, and proliferation, largely based on our latest findings. Finally, we will discuss the relevance of these novel mechanistic insights to ultimately realizing the translational potential of CAP1 in targeted therapeutics for breast cancer. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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30 pages, 1272 KiB

Open AccessReview

The Proliferative and Apoptotic Landscape of Basal-like Breast Cancer

by Sarah Alexandrou, Sandra Marie George, Christopher John Ormandy, Elgene Lim, Samantha Richelle Oakes and C. Elizabeth Caldon

Int. J. Mol. Sci. 2019, 20(3), 667; https://doi.org/10.3390/ijms20030667 - 4 Feb 2019

Cited by 22 | Viewed by 11302

Abstract

Basal-like breast cancer (BLBC) is an aggressive molecular subtype that represents up to 15% of breast cancers. It occurs in younger patients, and typically shows rapid development of locoregional and distant metastasis, resulting in a relatively high mortality rate. Its defining features are that it is positive for basal cytokeratins and, epidermal growth factor receptor and/or c-Kit. Problematically, it is typically negative for the estrogen receptor and human epidermal growth factor receptor 2 (HER2), which means that it is unsuitable for either hormone therapy or targeted HER2 therapy. As a result, there are few therapeutic options for BLBC, and a major priority is to define molecular subgroups of BLBC that could be targeted therapeutically. In this review, we focus on the highly proliferative and anti-apoptotic phenotype of BLBC with the goal of defining potential therapeutic avenues, which could take advantage of these aspects of tumor development. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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14 pages, 1524 KiB

Open AccessReview

Chemotherapy-Exacerbated Breast Cancer Metastasis: A Paradox Explainable by Dysregulated Adaptive-Response

by Justin D. Middleton, Daniel G. Stover and Tsonwin Hai

Int. J. Mol. Sci. 2018, 19(11), 3333; https://doi.org/10.3390/ijms19113333 - 26 Oct 2018

Cited by 57 | Viewed by 8588

Abstract

An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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20 pages, 644 KiB

Open AccessReview

Long Non-Coding RNAs as New Master Regulators of Resistance to Systemic Treatments in Breast Cancer

by Alma D. Campos-Parra, Eduardo López-Urrutia, Luz Tonantzin Orozco Moreno, César López-Camarillo, Thuluz Meza-Menchaca, Gabriela Figueroa González, Lilia P. Bustamante Montes and Carlos Pérez-Plasencia

Int. J. Mol. Sci. 2018, 19(9), 2711; https://doi.org/10.3390/ijms19092711 - 11 Sep 2018

Cited by 45 | Viewed by 5253

Abstract

Predicting response to systemic treatments in breast cancer (BC) patients is an urgent, yet still unattained health aim. Easily detectable molecules such as long non-coding RNAs (lncRNAs) are the ideal biomarkers when they act as master regulators of many resistance mechanisms, or of mechanisms that are common to more than one treatment. These kinds of markers are pivotal in quasi-personalized treatment selection, and consequently, in improvement of outcome prediction. In order to provide a better approach to understanding development of disease and resistance to treatments, we reviewed current literature searching for lncRNA-associated systemic BC treatments including endocrine therapies, aromatase inhibitors, selective estrogen receptor modulators (SERMs), trastuzumab, paclitaxel, docetaxel, 5-fluorouracil (5-FU), anthracyclines, and cisplatin. We found that the engagement of lncRNAs in resistance is well described, and that lncRNAs such as urotelial carcinoma-associated 1 (UCA1) and regulator of reprogramming (ROR) are indeed involved in multiple resistance mechanisms, which offers tantalizing perspectives for wide usage of lncRNAs as treatment resistance biomarkers. Thus, we propose this work as the foundation for a wide landscape of functions and mechanisms that link more lncRNAs to resistance to current and new treatments in years of research to come. Full article

(This article belongs to the Special Issue Molecular Biology and Pathology of Breast Cancer)

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