Breast cancer (BC) is a highly heterogeneous disease. The treatment of BC is complicated owing to intratumoral complexity. Tissue biopsy and immunohistochemistry are the current gold standard techniques to guide breast cancer therapy; however, these techniques do not assess tumoral molecular heterogeneity. Personalized medicine aims to overcome these biological and clinical complexities. Advances in techniques and computational analyses have enabled increasingly sensitive, specific, and accurate application of liquid biopsy. Such progress has ushered in a new era in precision medicine, where the objective is personalized treatment of breast cancer, early screening, accurate diagnosis and prognosis, relapse detection, longitudinal monitoring, and drug selection. Liquid biopsy can be defined as the sampling of components of tumor cells that are released from a tumor and/or metastatic deposits into the blood, urine, feces, saliva, and other biological substances. Such components include circulating tumor cells (CTCs), circulating tumor DNA (ctDNA) or circulating tumor RNA (ctRNA), platelets, and exosomes. This review aims to highlight the role of liquid biopsy in breast cancer and precision medicine.
Neoadjuvant chemotherapy (NAC) is often used to treat locally advanced disease for tumor downstaging, thus improving the chances of breast-conserving surgery. From the NAC response, it is possible to obtain prognostic information as patients may reach a pathological complete response (pCR). Those who do might have significant advantages in terms of survival rates. Breast cancer (BC) is a heterogeneous disease that requires personalized treatment strategies. The development of targeted therapies depends on identifying biomarkers that can be used to assess treatment efficacy as well as the discovery of new and more accurate therapeutic agents. With the development of new “OMICS” technologies, i.e., genomics, transcriptomics, and proteomics, among others, the discovery of new biomarkers is increasingly being used in the context of clinical practice, bringing us closer to personalized management of BC treatment. The aim of this review is to compile the main biomarkers that predict pCR in BC after NAC.
This study evaluated the effect of gestational low protein diet (LPD) and/or postnatal bisphenol A (BPA) exposure on mammary gland development and carcinogenesis in female offspring. Pregnant Sprague‐Dawley rats were fed a normal protein diet (NPD, 17% protein) or LPD (6% protein). At weaning, female offspring were distributed in four groups (NPD, LPD, NPD + BPA, and LPD + BPA) and received vehicle or BPA in drinking water (0.1%), during postnatal day (PND) 21 to 51. On PND 51, some female offspring were euthanized or received a single dose of 7,12‐dimethylbenzoanthracene (DMBA, 30 mg/kg, i.g.) and were euthanized on PND 250. On PND 51, neither gestational LPD nor postnatal BPA exposure, individually or in combination, significantly altered the development of mammary gland tree, mean number of terminal structures or estrogen receptor beta (ER‐β), proliferating cell nuclear antigen (PCNA) or caspase‐3 protein expression in the mammary tissue. A significant reduction in mammary epithelial area (%) was observed in both LPD groups and a significant increase in ER‐α protein expression was detected only in LPD group. In LPD + BPA group was observed a significant increase in both fat pad area (%) and in mean number of mammary epithelial cells positive for progesterone receptor (PR). On PND 250, the groups that received BPA presented lower latency and higher tumor incidence and tumor multiplicity and LPD + BPA group more aggressive tumors. These findings suggest that postnatal BPA exposure associated with gestational LPD is able to induce morphological changes in the mammary gland and increase susceptibility to mammary carcinogenesis.
INTRODUCTION: Breast cancer are the main cause of related deaths cancer among women, corresponding to 25% of new cases each year. When diagnosed at early stages, it has an overall five-year survival rate of up to 90%. However, in more advanced stages, survival is reduced to about 24%, with 90% of women in stage IV dying as a result of complications related to metastases. Considering that brain metastasis is an unfavorable prognostic site, and the identification of genetic-molecular profiles in primary tumors and in metastatic sites are a subject poorly described in the literature, we understand that the identification of mutational profiles may contribute to elucidate the genetic-molecular mechanisms associated with tumor progression. AIM: The aim of this study was to identify clonal and subclonal driver mutations that lead to evolution of metastatic clones from a breast cancer progression model. MATERIAL AND METHODS: For tumor progression model, automated extraction of DNA from buffy coat and paraffin samples of breast tumors and paired brain metastases (n=9) was performed. In the present work, we used a subclonal reconstruction model based on the combination of machine learning and population genetics concepts. This proposal is based on the frequency spectrum of each somatic mutation (SNVs or indels), considering VAF (Variant Allele Frequency - ratio of mapped reads of the mutant allele) in relation to the coverage of variant locus, as known as CCF (Cancer Cell Fraction). CCF is defined as the proportion of neoplastic cells that have a certain set of mutations and then is normalized considering the sample purity and the segments with changes in number of DNA copies (Copy Number Alterations). Then, a statistical model based on finite Dirichlet mixtures with mixed distributions is applied. In this model, Beta components capture clonal expansions and population genetics concepts were applied to mutant alleles in each population considering principles of cancer evolution. Finally, confidence was computed using both parametric and non-parametric bootstraps. The functions for building the model are implemented at https://caravagnalab.github.io/mobster/, and for visualization and construction of graphs, packages in R statistical-mathematical environment were used, such as ggplot2, sads, cli, clisymbols, cowplot, crayon, ctree, dndscv, dplyr, magrittr, reshape2, and tidyr. RESULTS: With this model was possible to identify the distribution of clones according to somatic alterations in patients with breast cancer and brain metastasis. It was possible to observe common patterns, such as alterations of the SF3B1 gene as a common ancestral clone in both conditions and the frequency of the AKT1 gene in a subclonal condition. Other genes relevant to breast cancer carcinogenesis, such as PIK3CA and TP53, are found in a different clonal hierarchical pattern between the two conditions. CONCLUSION: This data suggests a model of clonal evolution capable to identify which drivers clones and subclones are involved in the metastatic process. Citation Format: Muriele B. Varuzza, Adriane F. Evangelista, Cristiano P. Souza, Márcia C. Marques. TUMOR PROGRESSION MODEL IN BREAST CANCER WITH BRAIN METASTASIS [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-13-01.
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Toll-like receptors (TLRs) are essential type I transmembrane glycoproteins that play a major role in inflammation and innate immune system. TLRs have been investigated in cancer research due to their dual role in tumor progression. The TLRs signaling pathways can promote survival, cell proliferation and apoptosis and its stimulation may either enhance or inhibit tumor growth and metastasis. The role of TLR4 in cancer biology has been studied but the direct relation between TLR4 and development of many cancer types, including breast cancer, is still obscure. Thus, more studies about TLR4 expression in breast cancer can help to better understanding the involvement of TLR4 in this disease. The aim of this study was to investigate the expression of TLR4 in a rat mammary carcinogenesis model. At 51 days of age, female Sprague-Dawley rats were allocated into three groups: Groups 1 and 2 (n = 12 each) were initiated for mammary carcinogenesis by a single i.g. dose of 7,12-dimethylbenz[a]anthracene (DMBA) (80mg/kg) and Group 3 (n = 6) received a single i.g. dose of sesame oil (DMBA vehicle, 1 ml/kg). Also, group 2 received five s.c. injections per week of Tamoxifen (100 μg/kg) and groups 1 and 2 received similar injections of sesame oil (Tamoxifen vehicle, 0.5 ml/kg) during 12 weeks. At week 13, the animals were euthanized and mammary tumor (groups 1 and 2) and non-altered mammary glands (group 3) were collected and processed for histophatological analysis and TLR4 expression by immunohistochemistry. The TLR4 expression was classified as weak, moderate or strong and the incidence of intensity scores in tumor samples/group was analyzed by Fisher's exact test. Significant differences when p<0.05. Most of mammary tumors were classified as adenocarcinomas with tubular, papillary, cribriform or mixed patterns. Also, the tumors presented an expansive growth pattern with local invasive areas but without metastasis. Besides, a tumor inflammatory response was more intensively observed in G2. The immunoreactivity for TLR4 was significantly stronger in non-altered alveolar and ductal epithelial cells (G1) than in mammary tumor epithelial cells (groups 1 and 2) (p< 0.001 and p = 0.007, respectively). The TLR4 immunoreactivity was more intense in mammary tumor epithelial cells from tamoxifen-treated group than in positive control group (G1), but without a significant difference. In the tumor stroma the positivity for TLR4 was observed mainly in mononuclear inflammatory cells, showing a strong positivity for this marker in groups G1 and G2 when compared to the stromal cells from non-altered mammary tissue (G1, p = 0.028, p< 0,001). This present study show that there is a significant reduction in TLR4 expression in tumor epithelial cells when compared to the normal compartment in this rat DMBA-induced mammary carcinogenesis model. Besides, the intensity of the inflammatory response in the tumor microenvironment can alter the immunoreactivity for TLR4. Citation Format: Joyce Regina Zapaterini, Muriele Bertagna Varuzza, Nelci Antunes Moura, Maria Aparecida Marchesan Rodrigues, Luis Fernando Barbisan. Toll-like receptor 4 immunoreactivity in mammary tumors chemically induced in female Sprague-Dawley rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2720. doi:10.1158/1538-7445.AM2015-2720
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