ER81 Expression in Breast Cancers and Hyperplasia

ER81 is a transcription factor that may contribute to breast cancer; however, little known about the role of ER81 in breast carcinogenesis. To investigate the role of ER81 in breast carcinogenesis, we examined ER81 expression in IDC, DCIS, ADH, HUT, and normal breast tissues by immunohistochemical staining. We found that ER81 overexpression was detected in 25.7% (9/35) of HUT, 41.2% (7/17) of ADH, 54.5% (12/22) of DCIS, and 63.0% (51/81) of IDC. In 20 of breast cancer tissues combined with DCIS, ADH, and HUT, ER81 expression was found in 14/20 (70%) IDC. In these 14 cases all cases were ER81 positive expression in DCIS, 13 of 14 cases were positively expressed of ER81 in ADH and 8 of 14 were positive for ER81 in HUT components. A statistical significance was found between NBT and HUT () and HUT and ADH (). Clinical-pathological features analysis of breast cancer revealed that ER81 expression was significantly associated with Her2 amplification and was negatively associated with ER and PR expression. Our results demonstrated that ER81 overexpression was present in the early stage of breast development that suggested that ER81 overexpression may play an important role in breast carcinogenesis.

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Long non-coding RNA ARAP1-AS1 accelerates cell proliferation and migration in breast cancer through miR-2110/HDAC2/PLIN1 axis

Bioscience Reports ◽

10.1042/bsr20191764 ◽

2020 ◽

Vol 40 (4) ◽

Cited By ~ 1

Author(s):

Chong Lu ◽

Xiuhua Wang ◽

Xiangwang Zhao ◽

Yue Xin ◽

Chunping Liu

Keyword(s):

Breast Cancer ◽

Normal Breast ◽

Tumor Promoter ◽

Women Health ◽

Non Coding Rna ◽

Non Coding Rnas ◽

And Migration ◽

Breast Tissues ◽

Long Non Coding Rna

Abstract Breast cancer (BC) poses a great threaten to women health. Numerous evidences suggest the important role of long non-coding RNAs (lncRNAs) in BC development. In the present study, we intended to investigate the role of ARAP1-AS1 in BC progression. First of all, the GEPIA data suggested that ARAP1-AS1 was highly expressed in breast invasive carcinoma (BRAC) tissues compared with the normal breast tissues. Meanwhile, the expression of ARAP1-AS1 was greatly up-regulated in BC cell lines. ARAP1-AS1 knockdown led to repressed proliferation, strengthened apoptosis and blocked migration of BC cells. Moreover, ARAP1-AS1 could boost HDAC2 expression in BC through sponging miR-2110 via a ceRNA mechanism. Of note, the UCSC predicted that HDAC2 was a potential transcriptional regulator of PLIN1, an identified tumor suppressor in BC progression. Moreover, we explained that the repression of HDAC2 on PLIN1 was owing to its deacetylation on PLIN1 promoter. More importantly, depletion of PLIN1 attenuated the mitigation function of ARAP1-AS1 silence on the malignant phenotypes of BC cells. To sum up, ARAP1-AS1 serves a tumor-promoter in BC development through modulating miR-2110/HDAC2/PLIN1 axis, which may help to develop novel effective targets for BC treatment.

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Promoter Methylation Status of the Retinoic Acid Receptor-Beta 2 Gene in Breast Cancer Patients: A Case Control Study and Systematic Review

Breast Care ◽

10.1159/000489874 ◽

2019 ◽

Vol 14 (2) ◽

pp. 117-123 ◽

Cited By ~ 1

Author(s):

Kheirollah Yari ◽

Zohreh Rahimi

Keyword(s):

Breast Cancer ◽

Cancer Patients ◽

Retinoic Acid Receptor ◽

Methylation Status ◽

Normal Breast ◽

Breast Cancer Patients ◽

Retinoic Acid Receptor Beta ◽

Cancer Tissues ◽

Breast Tissues ◽

Receptor Beta

Background: We aimed to determine the promoter methylation status of the retinoic acid receptor-beta 2 (RARβ2) gene among breast cancer patients and to review relevant studies in this field in various populations. Methods: We analyzed 400 samples which comprised blood specimens from 102 breast cancer patients, 102 first-degree female relatives of patients, 100 cancer-free females, 48 breast cancer tissues, and 48 adjacent normal breast tissues from the same patients. The RARβ2 methylation status was determined using methylation-specific polymerase chain reaction (MSP) and DNA sequencing methods. Results: The presence of combined partially methylated (MU) and fully methylated (MM) forms of the RARβ2 gene (MU+MM) in the blood of patients was associated with susceptibility to breast cancer (odds ratio = 4.7, p = 0.05). A significantly higher frequency of the MM genotype was observed in cancer tissue (10.4%) compared to matched adjacent normal breast tissue (0%) (p = 0.02). Conclusion: We found a higher frequency of RARβ2 gene methylation in the blood and cancer tissues of patients compared to the blood of controls and adjacent normal breast tissues. The survey of studies on various populations demonstrated a higher RARβ2 methylation frequency in breast cancer patients compared to normal individuals, and many reports suggest a significant association between hypermethylation of the gene and susceptibility to breast cancer.

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Expression of MALAT1 Promotes Trastuzumab Resistance in HER2 Overexpressing Breast Cancers

Cancers ◽

10.3390/cancers12071918 ◽

2020 ◽

Vol 12 (7) ◽

pp. 1918

Author(s):

Yanyuan Wu ◽

Marianna Sarkissyan ◽

Ochanya Ogah ◽

Juri Kim ◽

Jaydutt V. Vadgama

Keyword(s):

Breast Cancer ◽

Cancer Progression ◽

Akt Pathway ◽

Breast Cancers ◽

Trastuzumab Resistance ◽

Mesenchymal Transition ◽

Cancer Tissues

Background: Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) is associated with cancer progression. Our study examined the role of MALAT1 in breast cancer and the mechanisms involved in the regulation of MALAT1. Methods: In vitro cell and in vivo animal models were used to examine the role of MALAT1 in breast cancer. The interaction of FOXO1 (Forkhead Box O1) at the promoter region of MALAT1 was investigated by chromatin immunoprecipitation (ChIP) assay. Results: The data shows an elevated expression of MALAT1 in breast cancer tissues and cells compared to non-cancer tissues and cells. The highest level of MALAT1 was observed in metastatic triple-negative breast cancer and trastuzumab-resistant HER2 (human epidermal growth factor receptor 2) overexpressing (HER2+) cells. Knockdown of MALAT1 in trastuzumab-resistant HER2+ cells reversed epithelial to mesenchymal transition-like phenotype and cell invasiveness. It improved the sensitivity of the cell’s response to trastuzumab. Furthermore, activation of Akt by phosphorylation was associated with the upregulation of MALAT1. The transcription factor FOXO1 regulates the expression of MALAT1 via the PI3/Akt pathway. Conclusions: We show that MALAT1 contributes to HER2+ cell resistance to trastuzumab. Targeting the PI3/Akt pathway and stabilizing FOXO1 translocation could inhibit the upregulation of MALAT1.

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Nuclear ING3 Expression Is Correlated With a Good Prognosis of Breast Cancer

Frontiers in Oncology ◽

10.3389/fonc.2020.589009 ◽

2021 ◽

Vol 10 ◽

Author(s):

Xiaoyan Wu ◽

Chuang Chen ◽

Bin Luo ◽

Dandan Yan ◽

Honglin Yan ◽

...

Keyword(s):

Breast Cancer ◽

Cox Regression ◽

Histological Grade ◽

Normal Breast ◽

Breast Cancer Patients ◽

Her2 Positive ◽

Positive Type ◽

Cox Regression Analysis ◽

Cancer Tissues ◽

Breast Tissues

The inhibitor of growth (ING) family was discovered as the type II tumor suppressors, which regulated the proliferation, apoptosis, differentiation, angiogenesis, metastasis, and invasion of tumor cells through multiple pathways. ING3, a new member of ING family, has been reported to be downregulated in several types of tumors. However, few studies on ING3 in breast cancer have been reported. In this study, we investigated the expression of ING3 and determined its prognostic value in breast cancer. The immunohistochemistry was performed to evaluate the expression of ING3 in tissue microarrays (TMA) including breast cancer tissues (n=211) and normal breast tissues (n=50). In normal breast tissues, ING3 protein was detected in both the cytoplasm and nucleus. In breast cancer tissues, ING3 protein was principally detected in the cytoplasm. Compared with normal breast tissues, the expression of ING3 in nucleus was remarkably reduced in breast cancer tissues. The downregulated ING3 in nucleus was significantly correlated with clinicopathological characteristics including histological grade, lymph node metastasis, and the status of ER and PR. In HER2 positive-type and triple-negative breast cancer (TNBC) patients, it had the lower rate of nuclear ING3 with high expression than that in luminal-type. Moreover, Kaplan-Meier curves demonstrated that the reduced expression of ING3 in nucleus was correlated with a poorer 5-DFS and 5-OS of breast cancer patients. Importantly, multivariate Cox regression analysis suggested that the reduced expression of ING3 in nucleus was an independent prognostic factor in breast cancer. Our study comprehensively described the expression of ING3 in breast cancer for the first time and proved that it was an independent prognostic predictor of breast cancer, as well as a new idea for study of breast cancer.

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Dual Aromatase-Sulphatase Inhibitors (DASIs) for the Treatment of Hormone Dependent Breast Cancer

Mini-Reviews in Medicinal Chemistry ◽

10.2174/1389557521666210119123840 ◽

2021 ◽

Vol 21 ◽

Author(s):

Laxmi Banjare ◽

Akhlesh Kumar Jain ◽

Suresh Thareja

Keyword(s):

Breast Cancer ◽

Dehydroepiandrosterone Sulfate ◽

Develop Breast Cancer ◽

Estrone Sulfate ◽

Cancer Tissues ◽

Breast Cancer Inhibition ◽

Estrogen Biosynthesis ◽

Breast Tissues ◽

Cancer Inhibition

: Breast cancer is the most frequent diagnosed cancer in women and the second most common form of cancer, causing death after lung cancer, all across the globe at an alarming rate. The level of estrogens, in breast cancer tissues of postmenopausal women is 10-40 folds higher than the non-carcinogenic breast tissues. As a result of this greater level of estrogen, breast tissue becomes more prone to develop breast cancer; mainly estradiol plays a significant role in the initiation and development of hormone dependent breast cancer. Androstenedione, Adrenal dehydroepiandrosterone sulfate and estrone-sulfate also plays an important role of precursor for estrogen biosynthesis. Estrogens deprivation exhibits an attractive phenomena in the advancement of most ideal therapeutics for the treatment of breast cancer. Inhibition of aromatase and sulphatase emerged as attractive therapy for the treatment of hormone dependent breast cancer via deprivation of estrogen by different pathways. The cocktail of aromatase and sulphatase inhibitors known as dual aromatase-sulphatase inhibitors (DASIs) emerged as an attractive approach for the effective estrogen deprivation. The present review article focused on the journey of dual aromatase-sulphatase inhibitors from the beginning to till date (2020). Keeping in view the key observations, this review may be helpful for medicinal chemists to design and develop new and efficient dual aromatase-sulphatase inhibitors for the possible treatment of hormone-related breast cancer.

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Genomic Changes in Normal Breast Tissue in Women at Normal Risk or at High Risk for Breast Cancer

Breast Cancer Basic and Clinical Research ◽

10.4137/bcbcr.s39384 ◽

2016 ◽

Vol 10 ◽

pp. BCBCR.S39384 ◽

Cited By ~ 5

Author(s):

David N. Danforth

Keyword(s):

Breast Cancer ◽

Gene Expression ◽

High Risk ◽

Breast Tissue ◽

Sporadic Breast Cancer ◽

Normal Breast Tissue ◽

Normal Breast ◽

Breast Carcinogenesis ◽

Molecular Changes ◽

Breast Tissues

Sporadic breast cancer develops through the accumulation of molecular abnormalities in normal breast tissue, resulting from exposure to estrogens and other carcinogens beginning at adolescence and continuing throughout life. These molecular changes may take a variety of forms, including numerical and structural chromosomal abnormalities, epigenetic changes, and gene expression alterations. To characterize these abnormalities, a review of the literature has been conducted to define the molecular changes in each of the above major genomic categories in normal breast tissue considered to be either at normal risk or at high risk for sporadic breast cancer. This review indicates that normal risk breast tissues (such as reduction mammoplasty) contain evidence of early breast carcinogenesis including loss of heterozygosity, DNA methylation of tumor suppressor and other genes, and telomere shortening. In normal tissues at high risk for breast cancer (such as normal breast tissue adjacent to breast cancer or the contralateral breast), these changes persist, and are increased and accompanied by aneuploidy, increased genomic instability, a wide range of gene expression differences, development of large cancerized fields, and increased proliferation. These changes are consistent with early and long-standing exposure to carcinogens, especially estrogens. A model for the breast carcinogenic pathway in normal risk and high-risk breast tissues is proposed. These findings should clarify our understanding of breast carcinogenesis in normal breast tissue and promote development of improved methods for risk assessment and breast cancer prevention in women.

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Estrogen receptor subtypes dictate the proliferative nature of the mammary gland

Journal of Endocrinology ◽

10.1530/joe-17-0582 ◽

2018 ◽

Vol 237 (3) ◽

pp. 323-336 ◽

Cited By ~ 15

Author(s):

Genevieve V Dall ◽

Samuel Hawthorne ◽

Yashar Seyed-Razavi ◽

Jessica Vieusseux ◽

Wanfu Wu ◽

...

Keyword(s):

Breast Cancer ◽

Estrogen Receptor ◽

Breast Cancer Risk ◽

Cancer Risk ◽

Breast Cancer Diagnosis ◽

Normal Breast ◽

Breast Development ◽

Receptor Subtypes ◽

Breast Cancers ◽

Proliferative Effect

Estrogen induces proliferation of breast epithelial cells and is responsible for breast development at puberty. This tightly regulated control is lost in estrogen-receptor-positive (ER+) breast cancers, which comprise over 70% of all breast cancers. Currently, breast cancer diagnosis and treatment considers only the α isoform of ER; however, there is a second ER, ERβ. Whilst ERα mediates estrogen-driven proliferation of the normal breast in puberty and breast cancers, ERβ has been shown to exert an anti-proliferative effect on the normal breast. It is not known how the expression of each ER (alone or in combination) correlates with the ability of estrogen to induce proliferation in the breast. We assessed the levels of each ER in normal mouse mammary glands subdivided into proliferative and non-proliferative regions. ERα was most abundant in the proliferative regions of younger mice, with ERβ expressed most abundantly in old mice. We correlated this expression profile with function by showing that the ability of estrogen to induce proliferation was reduced in older mice. To show that the ER profile associated with breast cancer risk, we assessed ER expression in parous mice which are known to have a reduced risk of developing ERα breast cancer. ERα expression was significantly decreased yet co-localization analysis revealed ERβ expression increased with parity. Parous mice had less unopposed nuclear ERα expression and increased levels of ERβ. These changes suggest that the nuclear expression of ERs dictates the proliferative nature of the breast and may explain the decreased breast cancer risk with parity.

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Progesterone receptors in normal breast development and breast cancer

Essays in Biochemistry ◽

10.1042/ebc20200163 ◽

2021 ◽

Author(s):

Sebastian Giulianelli ◽

Caroline A. Lamb ◽

Claudia Lanari

Keyword(s):

Breast Cancer ◽

Clinical Trials ◽

Progesterone Receptors ◽

Hormone Treatment ◽

Normal Breast ◽

Cancer Prognosis ◽

Breast Development ◽

Cancer Growth ◽

Breast Cancer Growth

Abstract Progesterone receptors (PR) play a pivotal role in many female reproductive tissues such as the uterus, the ovary, and the mammary gland (MG). Moreover, PR play a key role in breast cancer growth and progression. This has led to the development and study of different progestins and antiprogestins, many of which are currently being tested in clinical trials for cancer treatment. Recent reviews have addressed the role of PR in MG development, carcinogenesis, and breast cancer growth. Thus, in this review, in addition to making an overview on PR action in normal and tumor breast, the focus has been put on highlighting the still unresolved topics on hormone treatment involving PR isoforms and breast cancer prognosis.

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Differential Genomic Interactions Drive Progesterone Receptor Isoform Specific Functions in Breast Cancer

Journal of the Endocrine Society ◽

10.1210/jendso/bvab048.1673 ◽

2021 ◽

Vol 5 (Supplement_1) ◽

pp. A821-A821

Author(s):

Tram B Doan ◽

J Dinny Graham ◽

Mariah Tehan ◽

Barbara J Guild ◽

Christine L Clarke

Keyword(s):

Breast Cancer ◽

Progesterone Receptor ◽

Hormone Replacement ◽

Breast Cancer Incidence ◽

Normal Breast ◽

Breast Development ◽

Integrated Analysis ◽

Breast Cancers ◽

Multiple Cancer ◽

Breast Cancer Outcome

Abstract Progesterone is critical for normal breast development and function, and has been shown to stimulate proliferation of normal breast epithelial cells by increasing stem and progenitor cell numbers. Breast cancer incidence is increased in women exposed to progesterone analogues in combined estrogen plus progestin hormone replacement therapy, but not in women taking estrogen alone. Classical progesterone signaling is mediated through the nuclear progesterone receptor (PR), which occurs as two related but functionally different isoforms, PRA and PRB. PRA and PRB are co-expressed equally in normal breast tissue but become dysregulated in breast cancer where PRA often becomes predominant. PRA predominance in breast cancer is associated with poorer outcome and higher risk of distant metastasis in tamoxifen treated patients. We show using integrated analysis of ChIP-seq, ATAC-seq and transcriptomic profiling in a breast cancer cell line model of acquired PRA predominance that: 1) PRA and PRB have different requirements with regard to chromatin accessibility; 2) PRA predominance reshapes the PR cistrome and the associated transcriptome to affect genes not normally regulated by PR when PRA and PRB are equivalently expressed, possibly through assisted loading with multiple other transcription factors; 3) Genes regulated by PR only when PRA is predominant are associated with poorer breast cancer outcome and involved in multiple cancer-associated pathways including those that regulate cell proliferation and adhesion. Our data suggest a mechanism for the poorer disease outcome seen in breast cancers with a predominance of PRA.

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Molecular subtyping of breast cancer intrinsic taxonomy with oligonucleotide microarray and NanoString nCounter

Bioscience Reports ◽

10.1042/bsr20211428 ◽

2021 ◽

Author(s):

Yen-Jen Chen ◽

Ching-Shui Huang ◽

Nam-Nhut Phan ◽

Tzu-Pin Lu ◽

Chih-Yi Liu ◽

...

Keyword(s):

Breast Cancer ◽

Kappa Statistic ◽

Normal Breast ◽

Oligonucleotide Microarray ◽

Breast Cancers ◽

Luminal A ◽

Molecular Subtyping ◽

Luminal B ◽

Cross Platform ◽

Breast Tissues

Breast cancer intrinsic subtypes have been identified based on the transcription of a predefined gene expression (GE) profiles and algorithm (PAM50). This study compared molecular subtyping with oligonucleotide microarray and NanoString nCounter assay. A total of 109 Taiwanese breast cancers (24 with adjacent normal breast tissues) were assayed with Affymetrix Human Genome U133 plus 2.0 microarrays and 144 were assayed with the NanoString nCounter while 64 patients were assayed for both platforms. Subtyping with the nearest centroid (single sample prediction) was performed, and 16 out of 24 (67%) matched normal breasts were categorized as the normal breast-like subtype. For 64 breast cancers assayed for both platforms, 41 (65%, one unclassified by microarray) were predicted with an identical subtype, resulting in a fair Kappa statistic of 0.60. Taking nCounter subtyping as the gold standard, prediction accuracy was 43% (3/7), 81% (13/16), 25% (5/20), and 100% (20/20) for basal-like, HER2-enriched, luminal A and luminal B subtype predicted from microarray GE profiles. Microarray identified more luminal B cases from luminal A subtype predicted by nCounter. It’s not uncommon to use microarray for breast cancer molecular subtyping for research. Our study showed that fundamental discrepancy existed between distinct GE assays, and cross platform equivalence should be carefully appraised when molecular subtyping was conducted with oligonucleotide microarray.

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