Estrogen Biosynthesis and Action in Ovarian Cancer

Abstract

Ovarian cancer is still the deadliest of all gynecologic malignancies in women worldwide. This is attributed to two main features of these tumors, namely, (i) a diagnosis at an advanced tumor stage, and, (ii) the rapid onset of resistance to standard chemotherapy after an initial successful therapy with platin- and taxol-derivatives. Therefore, novel targets for an early diagnosis and better treatment options for these tumors are urgently needed. Epidemiological data show that induction and biology of ovarian cancer is related to life-time estrogen exposure. Also experimental data reveal that ovarian cancer cells share a number of estrogen regulated pathways with other hormone-dependent cancers, e.g., breast and endometrial cancer. However, ovarian cancer is a heterogeneous disease and the subtypes are quite different with respect to mutations, origins, behaviors, markers, and prognosis and respond differently to standard chemotherapy. Therefore, a characterization of ovarian cancer subtypes may lead to better treatment options for the various subtypes and in particular for the most frequently observed high-grade serous ovarian carcinoma. For this intention, further studies on estrogen-related pathways and estrogen formation in ovarian cancer cells are warranted. The review gives an overview on ovarian cancer subtypes and explains the role of estrogen in ovarian cancer. Furthermore, enzymes active to synthesize and metabolize estrogens are described and strategies to target these pathways are discussed.

Iron overload and altered iron metabolism in ovarian cancer

“…It is well-established that estrogen is associated with an increased risk of tumorigenesis in ovarian cancers (Liehr and Jones, 2001; Mungenast and Thalhammer, 2014; Jeon et al, 2016; Kyriakidis and Papaioannidou, 2016) as well as endometrial and breast cancers (Brown and Hankinson, 2015). Strikingly, there are links between estrogen and iron which stems from a hamster kidney tumor model in which the animals were implanted with estrogen and provided either normal chow or a diet with elevated iron levels which doubled tumor incidence (Wyllie and Liehr, 1998).…”

The role of menopausal hormone therapy in women with or at risk of ovarian and breast cancers: Misconceptions and current directions

“…Additionally, estrogens provide a microenvironment primed for tumor development by enhancing local vascular supply and favoring an immunosuppressive environment . Independent of ER activation, hormone metabolism generates free radicals that may act as mutagens …”

“…5,26 In the breast, fallopian tube, and ovary, the relative expression of receptors may contribute to tumorigenesis, and relative loss of ERβ is postulated to be a component of carcinogenesis. 27,28 Within the nucleus, estrogen binds to nuclear receptors directly associating with transcription factors to alter gene expression. Nuclear binding of ERα leads to transcriptional activation of multiple proto-oncogenes, including c-fos, c-myc, and HER2/neu; cell cycle regulating cyclins and growth factors.…”

“…29,30 Independent of ER activation, hormone metabolism generates free radicals that may act as mutagens. 5,27 The mechanisms of progesterone's role in breast and ovarian carcinogenesis are even less clear than that of estrogen. PR is expressed as two isoforms, PRA and PRB, which are usually expressed at a 1:1 ratio in normal tissues, the relative expression of which is driven by activation of the ER.…”

Treating gynecologic malignancies with selective estrogen receptor downregulators (SERDs): promise and challenges

“…Estrogen-induced proliferation with the accumulation of mutations resulting in metastatic transformation, estrogen action on the transmembrane GPER and downstream effects, and free radical species that result from estrogen metabolism are all mechanisms that have been postulated and are areas of ongoing investigation (2,4,164,165). Although ERRs have been implicated in the pathogenesis of endometrial cancer, little is known about these receptors in ovarian cancer.…”