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BRCA1 haploinsufficient Mesenchyme Derived from human peripheral blood Induced Pluripotent Stem Cell

ABSTRACT: BRCA1 molecule, known to be implicated in DNA repair and its alterations were associated to familial breast cancer prediposition. Genome of the patients with familial breast cancer predispostion harbor some germinal alterations in BRCA1 locus. Cells from peripheral blood of human with haplodeficiency BRCA1 locus and also from comparative sample (BRCA1 unaffected) were collected to produce induced pluripotent stem cell by classical protocol (Yamanaka OKSM) and Sendai Stem cell reprogammation which was validated by expression assessment of pluripotent stem cell markers and induction of teratoma after xenotransplantation mice model. Induced pluripotent stem cell (IPSC) were differentiated in mesenchymal lineage in order to see influence of BRCA1 effects during developmental steps of the stroma: effectively microenvironment of breast tumor is infiltrate of mesenchymal stromal cell. Total RNA of the mesenchyme derived IPS from control and BRCA1 haploinsufficient were respectively collected to screen whole expression analysis by transcriptome microarray.

ORGANISM(S): Homo sapiens

PROVIDER: GSE104693 | GEO | 2019/01/31

REPOSITORIES: GEO

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Project description:We have analyzed, using DNA microarrays, putative differences in gene-expression level between hereditary BRCA1 mutation-linked and sporadic breast cancer. Our results show that a previously reported marked difference between BRCA1-mutation linked and sporadic breast cancer was probably due to uneven stratification of samples with different ER status and basal-like versus luminal-like subtype. We observed that apparent difference between BRCA1-linked and other types of breast cancer found in univariate analysis was diminished when data were corrected for ER status and molecular subtype in multivariate analyses. In fact, the difference in gene expression pattern of BRCA1-mutated and sporadic cancer is very discrete. These conclusions were supported by the results of Q-PCR validation. We also found that BRCA1 gene inactivation due to promoter hypermethylation had similar effect on general gene expression profile as mutation-induced protein truncation. This suggests that in the molecular studies of hereditary breast cancer, BRCA1 gene methylation should be recognized and considered together with gene mutation. We analyzed 35 breast cancer specimens. Surgical samples obtained during mastectomy were flash-frozen in liquid nitrogen and stored at -80°C. Only samples from patients without neoadjuvant chemotherapy were used in this study as chemotherapy may seriously affect gene expression profile. All tissue samples were collected at the Pomeranian Medical University in Szczecin. Seventeen tumor samples were collected from patients with hereditary breast cancer: 12 were derived from tumors affecting women with hereditary BRCA1 mutation, the only one from a woman with BRCA2 mutation, while another eight cases had familial history of breast/ovarian cancer, but were negative for the BRCA1/2 mutations (so called BRCAx cases). Proportion of BRCA1 and BRCA2 mutated tumors was typical for the Polish population. Ten samples were derived from patients with apparently sporadic disease (no familial history of cancer) while 4 patients had a history of familial cancer aggregation (FCA) but without prevalence of breast/ovarian cancers. Thus, these samples were merged with sporadic samples in most of the analyses. All BRCA1 mutation-linked tumors in our study were negative for estrogen receptor (by immunohistochemistry, standard procedures for ER, PGR and HER2 staining were applied), while the only BRCA2-mutated tumor was ER-positive. There were 26 ductal and 5 medullary carcinomas within the study group, which is consistent with the distribution of histopathological types in BRCA1 mutation carriers. Patients were diagnosed at stage T1-2, N0-1 and M0. Caution: this submission contains the data from 6 microarrays done on the normal/pathologically unchanged breast tissue from breast cancer patiets. The data from normal tissues was not analyzed in the paper BRCA1-related gene signature in breast cancer is strongly influenced by ER status and molecular type by Lisowska et al., 2011, Front Biosci (Elite Ed). 2011 Jan 1;3:125-36

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BRCA1 haploinsufficient Mesenchyme Derived from human peripheral blood Induced Pluripotent Stem Cell

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