Ovarian cancer and DNA repair: DNA ligase IV as a potential key

Table 1 Hypothesis to epithelial ovarian cancer development

Hypothesis	Biological mechanism proposed	Epidemiological evidence
Incessant ovulation[24]	Repetitive ovulation and quickly cellular proliferation in post-ovulation repair creates a propitious environment to carcinogenesis initiation by genetic alteration accumulation as well as inclusion cysts development	Events that suppress ovulation such as pregnancy, lactation and oral contraceptive use are protective factors
	Ovulation inhibition results in gonadotropin and oxidative stress levels reduction, deceleration of ovarian follicle depletion and to a diminished inclusion cysts development in ovarian epithelium
Gonadotropins[91]	Excessive stimulation of ovarian epithelium by FSH and LH conducts to downstream genes activation as well as to stimulation of hormonal production by the ovary (as estrogen) in order to enhance cellular proliferation and consequently to malignant transformation and angiogenesis	Oral contraceptive use and pregnancy are protective. Hyper-gonadotropic conditions are common in infertile, in polycystic ovarian syndrome and in post-menopausal women
	The formation of a protective progestagenic hormonal milieu can stimulate apoptosis in genetically damaged ovarian epithelial cells, preventing tumor development
Hormonal stimulation[92]	High androgen levels are harmful while an increase in progesterone levels is benefic	Protective effect due to multiparity and oral contraceptive use. Harmful effect is associated with higher androgen levels as in polycystic ovarian syndrome women
Inflammation[25]	Ovulation is accomplished by an inflammatory response: redox potential alteration, cellular infiltration, cytokine release that can introduce DNA damage in epithelial cells involved in ovary rupture/repair	Inflammatory gynecological diseases, as endometriosis, can enhance EOC risk. Non-steroid anti-inflammatory drugs can be a protective factor

FSH: Follicle-stimulating hormone; LH: Luteinizing hormone; EOC: Epithelial ovarian cancer.