Epidemiological Study of Breast Cancer in Erbil, Kurdistan Region

Basic scientific background Breast cancer is one of the most common cancer and the most frequent cause of cancer death among women worldwide. Currently, subtyping breast cancers into hormone receptor (HR) positive, human epidermal growth factor receptor-2 overexpressing (HER2+), and triple negative breast cancer (TNBC) is the basis of diagnosing and treating this disease. The main treatment strategies for breast cancer include surgery, endocrine therapy, molecular targeted therapy, chemotherapy, radiotherapy, immunotherapy and gene therapy. However, resistance of breast cancer cells to chemotherapeutic agents, molecular targeted therapies and immunotherapy may occur either intrinsically or de nova, and is often ultimately responsible for treatment failure. Therefore, drug resistance poses a major challenge to breast cancer treatment. Current developments: Drug resistance in breast cancer is a complex clinical condition originating from a wide range of molecular alterations. The development of endocrine therapy resistance is believed to be associated with many cellular changes, such as ESR1 gene mutations, bypassing estrogen signaling pathway and altered tamoxifen metabolism. Meanwhile, changes in immune response, alternation of drug-binding property and downstream pathways are involved in the mechanisms of drug resistance in HER2+ breast cancer. In addition, resistance to chemotherapeutic agents predominantly arises from increased drug efflux and cross resistance. Current studies suggest that treatment strategies and therapeutics have to be designed specifically to each patient in different clinical situations. The use of modern genomic, proteomic and functional analytical techniques has contributed to identify novel genes and signaling networks involved in breast cancer drug resistance. Moreover, the use of high-throughput techniques in combination with bioinformatics and systems biology approaches has aided the interrogation of clinical samples and allowed the identification of molecular signatures and genotypes that predict responses to certain drugs. Despite much progress has been made in the field of breast cancer drug resistance, such as combination therapy and drug-loaded nanoparticles, the complexity and variability of drug resistance mechanism still inevitably lead to the continuous occurrence of drug resistance. Therefore, with the increasing amounts of anti-breast cancer agents, there are now unprecedented opportunities to understand and overcome drug resistance through further research into mechanisms and corresponding strategies, which will help achieve lasting disease control and bring survival benefits to patients with advanced cancer. Papers of interest: The current Research Topic of Frontiers in Pharmacology focuses on publishing Original Research, Review articles and Case Reports focusing on (a) elucidating mechanisms of drug resistance in breast cancer, target mutations, tumor microenvironment, undiscovered genes and signaling pathways; (b) promising drug delivery systems that can enhance the sensitivity of anti- breast cancer agents to various tumors; (c) strategies that can improve patient care during bio-chemotherapeutic treatments; (d) small molecule compounds that are effective against drug-resistant breast tumors (e) biomarkers of chemotherapy resistance in breast cancer patients and (f) in vitro and in vivo models. Guidelines for article of submission: - Authors must stick to the set guidelines for ethical practices by the Frontiers journals. - The main content of the article must have certain innovation and research significance. - The authors should describe the construction method of drug-resistant cell lines when using them for experiments in the article.

Many cancers might be influenced by obesity, including breast cancer, the leading cause of cancer death among women. Obesity is a complex state associated with multiple physiological and molecular changes capable of modulating the behavior of breast tumor cells and the surrounding microenvironment. This review discussed the inverse association between obesity and breast cancer among premenopausal breast cancer females and the positive association among postmenopausal. Four mechanisms may link obesity and breast cancer including leptin and leptin receptor expression, adipose chronic inflammation, sex hormone alternation, and insulin and insulinlike growth factor 1 (IGF-1) signaling. Leptin has been involved in breast cancer initiation, development, and progression through signaling transduction network. Leptin functions are strengthened through cross talk with multiple oncogenes, cytokines, and growth factors. Adipose chronic inflammation promotes cancer growth and angiogenesis and modifies the immune responses. A pro-inflammatory microenvironment at tumor site promotes cytokines and pro-inflammatory mediators adjacent to the tumor. Leptin stimulates pro-inflammatory cytokines and promotes T-helper 1 responses. Obesity is common of chronic inflammation. In obese patients, white adipose tissue (WAT) will promote pro-inflammatory mediators that will encourage tumor growth and WAT inflammation. Sex hormone alternation of estrogens is associated with increased risk for hormone-sensitive breast cancers. Estrogens cause tumorigenesis by its effect on signaling pathways that lead to DNA damage, stimulation angiogenesis, mutagenesis, and cell proliferation. In postmenopausal females, and due to termination of ovarian function, estrogens were produced extra gonadally, mainly in peripheral adipose tissues where adrenal-produced androgen precursors are converted to estrogens. Active estradiol leads to breast cancer development by binding to ERα, which is modified by receptor’s interaction of various signal transduction pathways. Hyperinsulinemia and IGF-1 activate the MAPK and PI3K pathways, leading to cancer-promoting effects. Cross talk between insulin/IGF and estrogen signaling pathways promotes hormone-sensitive breast cancer development. Hyperinsulinemia is a risk factor for breast cancer that explains the obesity-breast cancer association. Controlling IGF-1 level and targeting IGF-1 receptors among different breast cancer subtypes may be useful for breast cancer treatment. This review discussed several leptin signaling pathways, highlighting the potential advantage of targeting leptin as a potential target of the novel therapeutic strategies for breast cancer treatment.

Breast cancer is one of the most common malignant tumors in women and is the second leading cause of cancer deaths among women. The tumorigenesis and progression of breast cancer are not well understood. The existing researches have indicated that non-coding RNAs, which mainly include long non-coding RNA (lncRNA) and microRNA (miRNA), have gradually become important regulators of breast cancer. We aimed to screen the differential expression of miRNA and lncRNA in the different breast cancer stages and identify the key non-coding RNA using TCGA data. Based on series test of cluster (STC) analysis, bioinformatics analysis, and negatively correlated relationships, 122 lncRNAs, 67 miRNAs, and 119 mRNAs were selected to construct the regulatory network of lncRNA and miRNA. It was shown that the miR-93/20b/106a/106b family was at the center of the regulatory network. Furthermore, 6 miRNAs, 10 lncRNAs, and 15 mRNAs were significantly associated with the overall survival (OS, log-rank P < 0.05) of patients with breast cancer. Overexpressed miR-93 in MCF-7 breast cancer cells was associated with suppressed expression of multiple lncRNAs, and these downregulated lncRNAs (MESTIT1, LOC100128164, and DNMBP-AS1) were significantly associated with poor overall survival in breast cancer patients. Therefore, the miR-93/20b/106a/106b family at the core of the regulatory network discovered by our analysis above may be extremely important for the regulation of lncRNA expression and the progression of breast cancer. The identified key miRNA and lncRNA will enhance the understanding of molecular mechanisms of breast cancer progression. Targeting these key non-coding RNA may provide new therapeutic strategies for breast cancer treatment and may prevent the progression of breast cancer from an early stage to an advanced stage.

Breast cancer is one of the leading causes of cancer death in women. It is observed that hormonal, lifestyle and environmental factors that may increase the risk of breast cancer and often begins with cells in the milk-producing ducts (invasive ductal carcinoma), glandular tissue called lobules (invasive lobular carcinoma) or in other cells or tissue within the breast. The major signaling pathways involved in the breast cancer are Estrogen pathway, MAPK signaling pathway, PI3K/AKT signaling pathway, Notch signaling pathway, Wnt signaling pathway and P53 signaling pathway. Over the past decade, abnormal activation of Notch signaling in breast cancer has been stated by many different groups. In invasive breast cancer, the elevated expression of Notch signaling pathway components has been reported, including Jagged1-2, Dll1, Dll3, and Dll4, Notch receptor (Notch1 to Notch4). It is observed that increased JAG1-NOTCH4 signaling in human breast tumors is an important stimulator of cancer stem cells. The present investigation deals with the thorough understanding of molecular features of NOTCH4 protein emphasizing its key role in triggering the cancer pathway, by using different bioinformatics tools. The detailed insights into molecular features and the functional elements of NOTCH4 by analyzing its physicochemical parameters, secondary and tertiary structure prediction, domain analysis and intermolecular interactions, it can be considered as one of the potent drug target in breast cancer and can contribute to a novel alternate and promising treatment strategy for breast cancer through computer aided drug designing.

Background The clinicopathological classification was proposed in the St. Gallen Consensus Report 2011. We conducted a retrospective analysis of breast cancer subtypes, tumor-nodal-metastatic (TNM) staging, and histopathological grade to investigate the value of these parameters in the treatment strategies of invasive breast cancer. Methods A retrospective analysis of breast cancer subtypes, TNM staging, and histopathological grading of 213 cases has been performed by the methods recommended in the St. Gallen International Expert Consensus Report 2011. The estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER2), and Ki-67 of 213 tumor samples have been investigated by immunohistochemistry according to methods for classifying breast cancer subtypes proposed in the St. Gallen Consensus Report 2011. Results The luminal A subtype was found in 53 patients (24.9%), the luminal B subtype was found in 112 patients (52.6%), the HER2-positive subtype was found in 22 patients (10.3%), and the triple-negative subtype was found in 26 patients (12%). Histopathological grade and TNM staging differed significantly among the four subtypes of breast cancer (P &lt;0.001). Conclusion It is important to consider TNM staging and histopathological grading in the treatment strategies of breast cancer based on the current clinicopathological classification methods.

Introduction to epidemiology of breast and ovarian cancers

Current statistics show that breast cancer is the second leading cause of cancer deaths among American women. Therefore, there is a strong need to find improved treatment strategies for women suffering from this lethal disease. Though radiation and chemotherapy have been the frontline choice of treatment for cancer over the past few decades, due to the detrimental side effects, personalized treatment is rapidly rising as a superior treatment method. This is largely due to recent advances in genome-wide DNA sequencing that have allowed for the identification of cancer-related mutational landscapes. Through these studies, it has been found that up to 67% of breast cancer tumors carry a mutation in the Mediator subunit MED12 thus indicating that MED12 likely has a critical tumor suppressive role in breast cancer. Previous results from our lab, and others, have indicated that MED12 plays a critical role in restricting GLI3-dependent SHH signaling. This finding is of particular interest to this study since hyper-activated SHH signaling is known to play a major role in promoting breast cancer oncogenesis. Due to these findings, we hypothesize that mutations in MED12 cause hyper-activated SHH signaling in breast cancer to promote oncogenesis and, furthermore, that natural compounds could provide useful as a personalized treatment for MED12 mutant breast cancer. To study the effect of mutant MED12, a lentivirus carrying an shRNA against MED12 was generated and infected into MCF-7 cells. Since the vast majority of breast cancer-associated MED12 mutations lead to loss of protein function, the knockdown strategy through lentiviral shRNA is assumed to mimic the MED12 mutant setting. Proliferation assays were utilized to confirm that downregulated MED12 plays a role in the increased proliferation of breast cancer cells. Next, quantitative PCR was performed to determine the effect of downregulated MED12 on the expression of genes that are known to be regulated by GLI3. Finally, a screening strategy was employed by using a natural compound library to find potential novel treatment strategies for MED12 mutant breast cancer. Our findings confirmed that downregulation of MED12 increases proliferation of breast cancer cells in vitro thereby providing a strong argument that mutant MED12 would have the same effect. Through quantitative PCR it was confirmed that GLI3 target genes are upregulated in cancer cells when MED12 expression is low. Importantly, our natural compound screen identified several novel therapeutic compounds that specifically target MED12 downregulated breast cancer cells through a mechanism that involves SHH signaling. We therefore uncovered that MED12 mutations promote GLI3-dependent SHH signaling in breast cancer and, importantly, we identified potential novel therapeutic strategies for MED12 mutant breast cancer patients.

There is a critical need for superior breast cancer treatment since this disease remains the second leading cause of cancer deaths among American women. Though radiation and chemotherapy have been the frontline choice of treatment for cancer over the past few decades, due to the detrimental side effects, personalized treatment is rapidly rising as a superior treatment method. This is largely due to recent advances in genome‐wide DNA sequencing that have allowed for the identification of cancer‐related mutational landscapes. Through these technologies, MED12, a subunit of Mediator protein, has been found to be commonly mutated in a significant number of breast cancer patients. Therefore, uncovering the mechanistic basis behind MED12 mutant breast cancer is critical in order to find a personalized treatment regimen for this subclass of breast cancer. Previous work has shown that MED12 restricts GLI3‐dependent Sonic Hedgehog (SHH) signaling, a pathway that is often hyper activated in advanced breast cancer. We therefore hypothesize that mutated MED12 promotes GLI3‐dependent SHH signaling in breast cancer cells thereby promoting tumorigenesis and that this signaling pathway could be an effective therapeutic target in MED12 mutant breast cancer. To study the effect of mutant MED12, a lentivirus carrying an shRNA against MED12 was generated and infected into MCF‐7 cells. Since the vast majority of breast cancer‐associated MED12 mutations lead to loss of protein function, the knockdown strategy through lentiviral shRNA is assumed to mimic the MED12 mutant setting. Proliferation assays were utilized to confirm that downregulated MED12 plays a role in the increased proliferation of breast cancer cells. Next, quantitative PCR was performed to determine the effect of downregulated MED12 on the expression of genes that are known to be regulated by GLI3. Finally, a screening strategy was employed by using a natural compound library to find potential novel treatment strategies for MED12 mutant breast cancer. Our findings confirmed that downregulation of MED12 increases proliferation of breast cancer cells in vitro thereby providing a strong argument that mutant MED12 would have the same effect. Through quantitative PCR it was confirmed that GLI3 target genes are upregulated in cancer cells when MED12 expression is low. Importantly, our natural compound screen identified several novel therapeutic compounds that specifically target MED12 downregulated breast cancer cells through a mechanism that involves SHH signaling. We therefore uncovered that MED12 mutations promote GLI3‐dependent SHH signaling in breast cancer and we identified potential novel therapeutic strategies for MED12 mutant breast cancer patients.

Alternative splicing allows a gene to produce multiple proteins and is the main source of human proteome diversity. Aberrant regulation of alternative splicing produces proteins with different structures and can lead to altered protein function, inactivation, or deleterious variants, which can have severe effects on normal cellular function, leading to many diseases, including cancer. Alternative splicing abnormalities are often found in diseases, so alternative splicing is highly correlated with diseases and treatment. According to relevant statistics, breast cancer is an important factor that threatens women’s lives and health. A common sign of tumors in humans is abnormal alternative splicing. An increasing amount of evidence shows that abnormal alternative splicing plays an important role in the occurrence and development of breast cancer. At the same time, in the related treatment of breast cancer, alternative splicing can lead to the failure of existing treatment methods and induce drug resistance. Currently, targeted therapy is still the key strategy for breast cancer treatment. In this review, we discuss the five classifications of alternative splicing and aberrant alternative splicing in breast cancer. The role of alternative splicing in the drug resistance of breast cancer is also discussed. Evidence has shown that aberrant alternative splicing can lead to drug resistance to current therapies. Because splicing factors are involved in many aspects of cancer, splicing factors may provide a new strategy for cancer treatment and a powerful tool for progress in the fight against breast cancer. Antisense oligonucleotides form a double-stranded structure by complementary pairing with mRNA, which prevents the binding of mRNA and ribosomes, thus inhibiting protein synthesis. Therefore, after finding effective targets, antisense oligonucleotides can be applied in gene therapy, drug research and development, biological research, and other fields to improve therapeutic effects.

Breast cancer ranks as the most prevalent cancer globally, with lung and colorectal cancers following closely. Dysregulation of the cyclinD:CDK4/6:Rb axis has been shown to be a common feature in a number of human malignancies, including breast cancer. Targeting this pathway has emerged as a promising strategy for breast cancer treatment. Currently, the U.S. Food and Drug Administration has approved three CDK4/6 inhibitors for advanced hormone receptor-positive, HER2-negative breast cancer, when used in combination with endocrine therapy. However, there are still many breast cancer cases that do not qualify for these criteria and, therefore, do not benefit from CDK4/6 inhibitors prompting investigations into their potential synergy between CDK4/6 inhibitors with chemotherapy. Efforts are currently being made to test the application of these drugs in combination with chemotherapy. Previous studies have demonstrated a synergetic effect of combining CDK4/6 inhibitors and other therapies to treat breast and prostate cancers. While many studies administer these drugs concurrently, our hypothesis proposes a sequential combination approach. This method involves arresting cell cycle at the G0G1 phase using CDK 4/6 inhibitors and then releasing the drug when the cells are more vulnerable to chemotherapy treatment. Such an approach has the potential to expand the application of CDK4/6 inhibitors beyond ER+/HER2- breast cancer. The primary objective of this study is to evaluate the effectiveness of CDK4/6 inhibitors, both alone and in sequential combination with chemotherapy, across a range of breast cancer subtypes. Breast cancer cell lines (MDA-MB-231, HCC70 and T47D) were used in the study. For each cell line, a total of 3x105 cells were seeded in a 6-well plate, and after an overnight incubation, the media was changed with or without a CDK4/6 inhibitor (abemaciclib) and cultured for up to 72 hours. We monitored the drug's efficacy through flow cytometry and cell counting. Abemaciclib suppressed cell proliferation and cell cycle in G0G1 phase in the treated cells compared with the control. The results were similar in both receptor-positive and triple-negative breast cancer cell lines. The effect of abemaciclib was dose-dependent, and reversible at least 48 hours after drug withdrawal, suggesting an opportune time for administering chemotherapy. Future research will delve into investigating the efficacy of sequential treatment with chemotherapy after CDK 4/6 inhibitor withdrawal, utilizing 2D and 3D culture systems. Citation Format: Moses Kamita, Haythem Ali, Evelyn Jiagge, Jessica Bensenhaver, Eleanor Walker. Preclinical activity of CDK4/6 inhibitor alone or in sequential combination with chemotherapy using breast cancer cell line-derived organoid culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5722.

Breast cancer, as a heterogeneous disease, includes a wide range of pathological and clinical behaviors. Current treatment protocols, including radiotherapy, chemotherapy, and hormone replacement therapy, are mainly associated with poor response and high rate of recurrence. Therefore, more efforts are needed to develop alternative therapies for this type of cancer. Immunotherapy, as a novel strategy in cancer treatment, has a potential in treating breast cancer patients. Although breast cancer has long been considered problematic to treat with immunotherapy, as it is immunologically "cold," numerous newer preclinical and clinical reports now recommend that immunotherapy has the capability to treat breast cancer patients. In this review, we highlight the different immunotherapy strategies in breast cancer treatment.

Breast cancer, as a heterogeneous disease, includes a wide range of pathological and clinical behaviors. Current treatment protocols, including radiotherapy, chemotherapy, and hormone replacement therapy, are mainly associated with poor response and high rate of recurrence. Therefore, more efforts are needed to develop alternative therapies for this type of cancer. Immunotherapy, as a novel strategy in cancer treatment, has a potential in treating breast cancer patients. Although breast cancer has long been considered problematic to treat with immunotherapy, as it is immunologically "cold," numerous newer preclinical and clinical reports now recommend that immunotherapy has the capability to treat breast cancer patients. In this review, we highlight the different immunotherapy strategies in breast cancer treatment.

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Breast cancer is the leading cause of cancer deaths in females all over the world, mainly resulting from metastasis. Previous studies have revealed that repressor element-1 (RE-1) silencing transcription (REST) acted as a tumor suppressor in breast cancer. However, the mechanism by which REST is regulated remains unknown, and its role in the metastasis in breast cancer cells remains unclear. In the present study, we showed that the expression of REST was lower in breast cancer samples than that of adjacent samples by immunohistochemical analysis, which may be due to hypermethylation of the REST promoter. Low REST levels are significantly associated with malignant progression in breast cancer patients. Additionally, we elucidated the functions of REST on proliferation and invasion in breast cancer cells. Lentivirus transfection was used to overexpress REST in human breast MDA-MB-231 cells. Then the biologic consequences of overexpressing REST in regard to cell proliferation, apoptosis, and invasion were determined. Furthermore, we also determined matrix metalloproteinase-9 (MMP9) as a target of REST. These results demonstrate that downregulation of REST, a tumor suppressor in breast cancer, is associated with hypermethylation. Induced REST expression is capable of attenuating invasion ability of breast cancer cells, which may be a novel strategy for metastatic breast cancer treatment.

The Breast