Abstract
Endometriosis is a common gynecological disease affecting 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue in localizations outside of the uterine cavity as, e.g., endometriotic ovarian cysts. Mainly, two epithelial ovarian carcinoma subtypes, the ovarian clear cell carcinomas (OCCC) and the endometrioid ovarian carcinomas (EnOC), have been molecularly and epidemiologically linked to endometriosis. Mutations in the gene encoding the AT-rich interacting domain containing protein 1A (ARID1A) have been found to occur in high frequency in OCCC and EnOC. The majority of these mutations lead to a loss of expression of the ARID1A protein, which is a subunit of the SWI/SNF chromatin remodeling complex and considered as a bona fide tumor suppressor. ARID1A mutations frequently co-occur with mutations, leading to an activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway, such as mutations in PIK3CA encoding the catalytic subunit, p110α, of PI3K. In combination with recent functional observations, these findings strongly suggest cooperating mechanisms between the two pathways. The occurrence of ARID1A mutations and alterations in the PI3K/AKT pathway in endometriosis and endometriosis-associated ovarian carcinomas, as well as the possible functional and clinical implications are discussed in this review.
Highlights
The identification of recurrent somatic mutations in endometriosis-associated ovarian cancer, in particular, AT-rich interacting domain containing protein 1A (ARID1A) mutations [1,2], provided the first molecular evidence of a direct pathogenic link between endometriosis and certain subtypes of ovarian carcinomas [3,4].Endometriosis is a common gynecological inflammatory disease that affects at least 6%–10% of women of reproductive age and is characterized by the presence of endometrial-like tissue outside of the uterine cavity [5,6]
36 cases of solitary ovarian endometriosis; Loss of ARID1A expression in 20% of benign normal eutopic endometrium as control endometriomas; normal endometrium retained. This observation sustains the theory of ARID1A being a tumor suppressor in which loss of expression occurs in cell clones that are undergoing a process of precancerous alteration
Seventy-five percent (24/32) of gastric cancers with ARID1A mutations immunohistochemically exhibited a loss or substantially lower ARID1A protein expression compared to cancers with the wild-type gene (p < 0.001) [91]. These results suggest that an immunohistochemical loss of ARID1A expression correlates well, not perfectly, with truncating ARID1A mutations, which justifies its use as a surrogate marker for the underlying gene mutations [87,101,104,107,108,109]
Summary
Activation of the phosphatidylinositol 3-kinase (PI3K)/AKT pathway supports multiple mechanisms responsible for cancer progression, including proliferation, inhibition of apoptosis, cell adhesion and transformation. The response to decidual stimuli by medroxyprogesterone acetate and dibutyryl cAMP was dramatically lower in ectopic endometriotic stromal cells Both inhibition of PI3K and AKT led to increasing nuclear FOXO1 and IGFBP1 levels in response to treatment with medroxyprogesterone acetate and dibutyryl cAMP, supporting evidence that the increased PI3K/AKT pathway is involved in the reduced decidual response in endometriosis [113]. This observation is further interesting, since it may indicate that the PI3K/AKT pathway is involved in processes supporting the effects of progesterone resistance, a well-described characteristic of endometriosis [127]. Preclinical and clinical phase-I studies have suggested that inhibition of this pathway may help to overcome resistance to chemotherapy in ovarian cancer [132], which is a common problem in OCCC and, would be of specially great interest in this tumor type [52]
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