**1. Introduction**

Ovarian cancer (OC) is a gynecological malignancy that commonly originates from the ovaries, fallopian tubes, and peritoneum [1] and is considered as the most lethal malignancy with a high rate of chemoresistance and relapses. Regarding their histology, 90% of ovarian tumors are of the epithelial type [2].

Endometriosis represents a precursor lesion for certain types of epithelial OC, being related to microenvironment changes (such as estrogen production and dependency, progesterone resistance, and inflammation), which lead to genetic alterations and/or genetic susceptibilities that favour endometriosis-associated ovarian carcinogenesis [2–4]. It has been demonstrated that ovarian endometriosis, ovarian atypical endometriosis, and

**Citation:** Lozneanu, L.; Balan, R.A.; P˘av˘aleanu, I.; Giu¸sc˘a, S.E.; C˘aruntu, I.-D.; Amalinei, C. BMI-1 Expression Heterogeneity in Endometriosis-Related and Non-Endometriotic Ovarian Carcinoma. *Int. J. Mol. Sci.* **2021**, *22*, 6082. https://doi.org/10.3390/ ijms22116082

Academic Editor: Antonio Simone Laganà

Received: 26 April 2021 Accepted: 30 May 2021 Published: 4 June 2021

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**Copyright:** © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

endometriosis-related OC (EOC) share the same genetic alterations and express clonality, while the ovarian malignant endometriosis-associated phenotype is promoted by chronic inflammation, which provides permanent mutations and nonpermanent cytokine production [2]. The different clinicopathological features and distinct mutational statuses justify the classification of OC into EOC, represented mainly by clear cell and endometrioid subtypes, and non-endometriotic OC (NEOC) [5].

OC is commonly diagnosed in advanced stages III and IV when the tumor has a high potential of metastasis [6]. Therefore, the early detection of OC by using different biomarkers is an important clinical desideration. Concomitantly, the researchers' interest is directed towards a deep insight into the genetic and molecular substrate of ovarian carcinogenesis, aiming not only to understand the sequence of carcinogenic events, but also to identify new potential prognostic factors and therapeutic targets. The exclusive recent list of potential candidate biomarkers includes molecules expressed by the cancer stem and stem-like cells [7], BMI-1 protein being one of them [8,9]. BMI-1 protein, a stemlike marker, represents a homologue of the *Drosophila polycomb* group of proteins, and its role is the regulation of homeotic genes expression by transcription repression [10]. The BMI-1 gene has been initially isolated as an oncogene, which cooperates with c-Myc in lymphoma experimental models [11]. It belongs to the Polycomb-group (PcG) of proteins, which are involved in axial pattern establishment, hematopoiesis, cementogenesis, and senescence [11].

Considering BMI-1's involvement in cellular proliferation and tumor progression, this gene has been identified, as expected, in a large variety of human tumors, such as: lymphoma [12–14], brain [15], prostate [16], oropharynx and nasopharynx [10,17,18], breast [19,20], bladder [11], gastric [21], pancreas [22], esophagus [23], lungs [24,25], head and neck cancers [26], malignant melanoma [27], pleomorphic adenoma [28], and also displaying a prognosis value in mielodysplastic syndromes [29] and in gallbladder cancer [30]. Although its action has been initially thought to be achieved by p16 suppressor gene repression, subsequent studies have demonstrated another specific mechanism of action by intercellular adhesion pathway modulation [31].

Limited information is available about BMI-1 in OC, as few studies address this topic, mainly providing experimental evidences [10,32–41]. BMI-1 increased expression mirrors an early and maybe reversible event in carcinogenesis [10], suggestive for an invasive and aggressive phenotype during tumor development [10,42]. It is demonstrated that BMI-1 regulates cell cycle and promotes cell proliferation, which has self-renewal and differentiation potential [9], acts as a potential modulator of cellular adhesion in endometriotic tumor cells, and alters endometrial stromal cells by changing microenvironment interactions in OC [43]. Several results support its potential value as an independent predictor for poor outcomes [39] and as a possible new therapeutic target in chemoresistant OC [7,9,33,40,41].

Currently, there is a high interest in a better understanding and characterization of EOC, in an attempt to provide a different clinical and therapeutic management compared to that of NEOC. In this regard, the purpose of our study was to evaluate the immunohistochemical (IHC) BMI-1 expression in two different groups of OC (associated or not with endometriosis), aiming to identify the differences in its tissue profile. The novelty of this research consisted in a double assessment of BMI-1, in tumor epithelial cells and stromal cells, following the potentiation relationship of these two cell types in tumor progression. Nevertheless, the BMI-1 expression was correlated with clinicopathological data that offer a solid functional image of the tumor progression.
