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Breast cancer (BC) is the most common form of cancer, leading to high mortality rates among women worldwide. In this study we have analyzed mRNA expression of 15-hydroxy-prostaglandin-dehydrogenases (15-HPGD), cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) and miRNAs (miR-21, miR-155) in three cell lines of estrogen-positive human breast carcinomas (MCF-7, BT-474, ZR-75-1). Results of three independent experiments have demonstrated significantly higher levels of COX-2 and COX-1 mRNAs in the cell line ZR-75-1 cells than in MCF-7 and BT-474 cells. mRNA levels of total 15-HPGD and functional-15-HPGD were lower in BT-474 than in MCF-7 and in ZR-75-1 cells. Synthesis of the 15-HPGD enzyme in BT-474 cells was blocked at the level of nuclear processing of an immature pre-mRNA. High expression of miR-21 was detected in all the tumor cell lines (MCF-7, ZR-75-1 and BT-474). In the breast cancer cell lines, the expression level of miR-155 was significantly lower than that of miR-21. Correlations have been found between dysregulation of miR-21, miR-155 and mRNA levels of 15-HPGD, COX-1, COX-2. The results obtained in this study showed that miR-21 and miR-155 regulate activity of several genes in the tumor cell and on some genes they exhibited a cumulative effect. Based on these results, we concluded that the miR-21 and miR-155 inhibit activity of the tumor suppressor gene 15-HPGD and induce a potential oncogene COX-2, which contributes to malignancy and metastasis of breast cancer cells.