OC is an extremely rare type of breast cancer, characterized by mitochondrial accumulation. In our patient's tumor, we demonstrated significant changes in the expression of miR-146a-5p and Bcl-2 in OC compared to that of IDC, which suggests that miR-146a-5p, by targeting Bcl-2, has a potential therapeutic effect on OC.
The World Health Organization classification defines OC of the breast as a tumor in which more than 70% of all cells have oncocytic features . The distinctive feature of oncocytes is the enlargement of cells containing abundant eosinophilic granules in their cytoplasm due to an increase in altered mitochondria . Morphologically, OC resembles apocrine carcinoma, which also has an abundant eosinophilic granular cytoplasm . On hematoxylin and eosin staining, it is difficult to distinguish OC from apocrine carcinoma based on morphological features. Thus, accurate diagnosis of OC necessitates immunohistochemical staining for several markers, including mitochondrial markers. In addition, GCDFP-15, a marker for apocrine differentiation, must be absent for the diagnosis of OC. In our patient, the morphologic features and use of immunostaining for antimitochondrial markers and GCDFP-15 were consistent with OC.
The mechanism of oncocytic tumor formation remains to be fully elucidated. Mitochondrial DNA mutations or mitochondrial genome alterations have been found in OC, which lead to alterations in mitochondrial metabolism and tumorigenesis [19, 20]. However, these observations have not been investigated in OC of the breast, and the unique miRNA expression in OC of the breast is poorly described because of its rarity. In other organs in which OC has been reported, such as the thyroid, kidneys, and salivary glands, miR-146a-5p expression has not been found. In relation to miR-146a and oncocytes, Fridman et al. demonstrated a specific downregulation of miR-146a in renal oncocytoma in comparison with other histological types of renal tumors . Other investigators have detected miRNAs in multiple subcellular compartments, including the mitochondria [22–24]. Regarding the accumulation of mitochondria as the hallmark of OC, we hypothesized that the expression of mito-miR would be altered in OC, in contrast to IDC. Indeed, our data showed that the expression of miR-146a-5p, a mito-miR, was significantly decreased in OC compared to that in IDC. We found no evidence that the altered expression of miR-146a-5p is associated with carcinogenesis of oncocytes; however, our results raise the possibility of a connection between miR-146a-5p dysregulation and mitochondrial abnormality in OC of the breast.
In breast cancer, miR-146a-5p has been shown to be upregulated, promoting proliferation and invasion and inducing epithelial–mesenchymal transition [25, 26]. Furthermore, upregulation of miR-146a-5p plays an important role in regulating Bcl-2 proteins via the mitochondrial pathway of apoptosis in aging-related diseases, including cancer . Bcl-2 proteins exist in the outer membrane of mitochondria and their overexpression in breast cancer has been shown to increase invasion and migration [27, 28]. The higher expression of Bcl-2 and lower expression of miR-146a-5p in OC tissues compared to IDC tissues in our study indicate that miR-146a-5p may contribute to altered expression of Bcl-2 through mitochondria.
Our study has several limitations. First, we investigated only one sample of OC; we could not obtain multiple OC samples because of its rarity. We acknowledge that our results would be insufficient to generalize to all cases of OC; however, providing descriptions of molecular profiling in a fresh sample is important and beneficial for patients with very rare tumors, from both clinical and translational standpoints . In addition, although investigations of both tumors and noncancerous samples would be more desirable, we could not obtain noncancerous fresh samples for experimentation. Finally, we could not identify the mechanisms underlying the association between miR-146a-5p and Bcl-2 in OC in this study. Further studies are needed to confirm these findings.
OC is a rare type of breast cancer. To the best of our knowledge, significant changes in the expression of miR-146a-5p and Bcl-2 in OC, in comparison with IDC, have not been previously reported. Therefore, our findings could help improve the understanding of this rare tumor.