RESUMO
BACKGROUND: Strategies for breast cancer prevention in women with germline BRCA1/2 mutations are limited. We previously showed that recombinant human chorionic gonadotropin (r-hCG) induces mammary gland differentiation and inhibits mammary tumorigenesis in rats. The present study investigated hCG-induced signaling pathways in the breast of young nulliparous women carrying germline BRCA1/2 mutations. METHODS: We performed RNA-sequencing on breast tissues from 25 BRCA1/2 mutation carriers who received r-hCG treatment for 3 months in a phase II clinical trial, we analyzed the biological processes, reactome pathways, canonical pathways, and upstream regulators associated with genes differentially expressed after r-hCG treatment, and validated genes of interest. RESULTS: We observed that r-hCG induces remarkable transcriptomic changes in the breast of BRCA1/2 carriers, especially in genes related to cell development, cell differentiation, cell cycle, apoptosis, DNA repair, chromatin remodeling, and G protein-coupled receptor signaling. We revealed that r-hCG inhibits Wnt/ß-catenin signaling, MYC, HMGA1 , and HOTAIR , whereas activates TGFB/TGFBR-SMAD2/3/4, BRCA1, TP53, and upregulates BRCA1 protein. CONCLUSION: Our data suggest that the use of r-hCG at young age may reduce the risk of breast cancer in BRCA1/2 carriers by inhibiting pathways associated with stem/progenitor cell maintenance and neoplastic transformation, whereas activating genes crucial for breast epithelial differentiation and lineage commitment, and DNA repair.
Assuntos
Neoplasias da Mama , Mama , Humanos , Feminino , Ratos , Animais , Gonadotropina Coriônica/genética , Gonadotropina Coriônica/farmacologia , Neoplasias da Mama/genética , Neoplasias da Mama/prevenção & controle , Neoplasias da Mama/metabolismo , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Transformação Celular Neoplásica/genética , Mutação , Transdução de SinaisRESUMO
Full-term pregnancy at an early age confers long-term protection against breast cancer. Published data shows a specific transcriptomic profile controlling chromatin remodeling that could play a relevant role in the pregnancy-induced protection. This process of chromatin remodeling, induced by the breast differentiation caused by the first full-term pregnancy, has mainly been measured by the expression level of genes individually considered. However, genes equally expressed during the process of chromatin remodeling may behave differently in their interaction with other genes. These changes at the gene cluster level could constitute an additional dimension of chromatin remodeling and therefore of the pregnancy-induced protection. In this research, we apply Information and Graph Theories, Differential Co-expression Network Analysis, and Multiple Regression Analysis, specially designed to examine structural and informational aspects of data sets, to analyze this question. Our findings demonstrate that, independently of the changes in the gene expression at the individual level, there are significant changes in gene-gene interactions and gene cluster behaviors. These changes indicate that the parous breast, through the process of early full-term pregnancy, generates more modules in the networks, with higher density, and a genomic structure performing additional and more complex functions than those found in the nulliparous breast.
Assuntos
Neoplasias da Mama/genética , Epistasia Genética/genética , Genômica , Transcriptoma/genética , Neoplasias da Mama/patologia , Diferenciação Celular/genética , Células Epiteliais/metabolismo , Feminino , Regulação da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Análise de Sequência com Séries de Oligonucleotídeos , Pós-Menopausa/genética , GravidezRESUMO
We present a computational-statistical algorithm that, from data on the staining degree of immunocytochemical markers: i) evaluates the ability of the considered immuno-panel in predicting the breast cancer stage; ii) makes the accurate identification of breast cancer stage possible; iii) provides the best stage prognosis compatible with the considered sample; and iv) does so through the use of the minimum number of markers minimizing time and resource costs. After running the algorithm on two data sets [triple-negative breast cancer, (TNBC), and estrogen receptor-negative breast cancer, (ERNBC)], we conclude that EpCAM and ß1 integrin are enough to accurately predict TNBC stage, being ALDH1, CD24, CD61, and CK5 the necessary markers to exactly predict ERNBC stage.
