Microrna Involved In Carcinogenesis Of Breast Cancer And Hereditary Breast Cancer

[Background]Flat epithelial atypia (FEA) of the breast is characterised by a few layers of mildly atypical luminal epithelial cells. Genetic changes found in ductal carcinoma in situ (DCIS) and invasive ductal breast carcinoma, not otherwise specified (IDC-NOS) are also found in FEA, albeit at a lower concentration. So far, miRNA expression changes associated with invasive breast cancer, like miR-21, have not been studied in FEA.[Methods](1)51 cases of FEA were selected from 270 cases of DCIS with FEA components. The cases were divided into 4 grades and 2 groups, and immunohistochemical study for ER, PR,α-SMA, p63, p53, bcl-2, Her-2, cyclinD1 and Ki-67 was performed on these cases.(2) We performed miRNA in-situ hybridization (ISH) on 15 cases with simultaneous presence of normal breast tissue, FEA and/or DCIS and 17 additional cases with IDC-NOS. Expression of the miR-21 targets PDCD4, TM1 and PTEN was investigated by immunohistochemistry.[Results](1) The cases of gradeⅠ-Ⅳof FEA were 28,8,6 and 9, respectively. There were 24 cases of FEA located in the same quadrant with DCIS and 27 cases in the different quadrant. The proportion of FEA in the same quadrant with DCIS increased with the grade of FEA (gradeⅠ,Ⅱ,Ⅲ,Ⅳwere 28.6%,37.5%,66.7%,100%, respectively). Immunohistochemically, myoepithelial cells of FEA appeared attenuated stained with a-SMA and p63. The positive rate of FEA for ER, PR, p53, bcl-2, Her-2, cyclinD1 and Ki-67 were 62.8%,54.9%,21.6%,62.8%,15.7%,62.8% and 35.3%, respectively. There were significant difference in the expression of Her-2, cyclinDl and Ki-67 among low grade FEA, high grade FEA and DICS, and the positive rate of Her-2, cyclinD1 and Ki-67 were significantly higher in high grade FEA and DICS than in low grade FEA. There were significant difference in the expression of Her-2, cyclinD1 and Ki-67 among FEA in the same quadrant with DCIS, FEA in the different quadrant with DCIS and DICS, and the positive rate of Her-2, cyclinD1 and Ki-67 were significantly lower in FEA in the different quadrant with DCIS than in DCIS.(2) Two out of fifteen cases showed positive staining for miR-21 in normal breast ductal epithelium, seven out of fifteen cases were positive in the FEA component and nine out of twelve cases were positive in the DCIS component. A positive staining of miR-21 was observed in 15 of 17 IDC-NOS cases. In 12 cases all three components were present in one tissue block and an increase of miR-21 from normal breast to FEA and to DCIS was observed in 5 cases. In three cases the FEA component was negative, whereas the DCIS component was positive for miR-21. In three other cases, normal, FEA and DCIS components were negative for miR-21 and in the last case all three components were positive. Overall we observed a gradual increase in percentage of miR-21 positive cases from normal, to FEA, DCIS and IDC-NOS. Immunohistochemical staining for PTEN revealed no obvious changes in staining intensities in normal, FEA, DCIS and IDC-NOS. Cytoplasmic staining of PDCD4 increased from normal to IDC-NOS, whereas, the nuclear staining decreased. TM1 staining decreased from positive in normal breast to negative in most DCIS and IDC-NOS cases. In FEA, the staining pattern for TM1 was similar to normal breast tissue.[Conclusions](1) The position relation between FEA and DCIS is closer with the higher grade of FEA. We should take FEA, especially FEA which is high grade and adjacent to DCIS, as a precancerous lesion.(2) Upregulation of miR-21 from normal ductal epithelial cells of the breast to FEA, DCIS and IDC-NOS parallels morphologically defined carcinogenesis. No clear relation was observed between the staining pattern of miR-21 and its previously reported target genes. [Background]BRCA1 associated breast cancer has its own distinctive clinical features, histopathologic character, copy number alterations and gene expression profiles in comparison with sporadic breast cancer and BRCA2 associated cancer. MicroRNAs (miRNAs) play an important role in a series of biopathological functions, such as growth, development, apoptosis, proliferation and carcinogenesis. We aimed to explore the miRNA expression profiles in BRCA1 associated cases compared with BRCA1 non-associated cases.[Methods]MiRNA microarray method was applied to investigate the miRNA expression profiles of BRCA1 associated and non-associated breast cancer cases. Eight BRCA1 mutation cases, ten BRCA1/2 non-mutation sporadic breast cancer cases and 6 normal breast cases (pooled into two samples) were included and compared with 328 flagged miRNAs in our study.[Results]A subgroup of miRNAs was identified between BRCA1 mutation cases and BRCA1 non-mutation cases. With the help of Targetscan software, certain miRNAs were further selected among them, which might play a potential role in BRCA1 pathway.[Conclusions]Compared with BRCA1/2 non-mutation sporadic breast cancer cases and normal cases, BRCA1 mutation cases show a distinctive miRNA expression profiles by hierarchical cluster analysis.