Ovarian steroids and cancer: news on the breast, questions on the reproductive tract

Abstract

The association between steroid hormones and cancer has been a primary research focus for many years. Reproductive hormones are of particular interest given the fact that several highly prevalent cancers in women, such as breast or endometrial cancer [1], are paradigmatic examples of endocrine-related cancer. Experimental and clinical studies further support this link. What is less clear is the association between ovarian steroids and ovarian cancer, although some epidemiological studies suggest a possible hormonal background [2]. The reproductive hormones exerting the strongest modulatory influence on cancer risk are estrogens and progestogens, while the role of androgens seems somewhat debatable [3]. Estrogens have been central for many years, with an assigned role as promotors of carcinogenesis in both breast and endometrium. This concept has been reinforced by a wealth of data, from experimental models in which estrogens exhibited a proliferative effect, to epidemiological studies showing a higher risk in women who experience a later menopause onset and a reduced risk in users of aromatase inhibitors [4] or selective estrogen receptor modulators like tamoxifen or raloxifene [5]. Progestogens, in turn, have been taken as counterbalancing agents, with a clear antiproliferative action in the endometrium, and for some time this was seen to extend to the breast. Initial data showing higher mitotic action in breast biopsies during the luteal phase and clearer findings from clinical studies published this century have come to challenge that notion. Indeed, it has become persistently observed that used alone or in combination with estrogens, progestogens increase the risk of breast cancer, and this effect is substantially stronger than that of estrogens [6]. Until recently, the molecular details of the oncogenic effect of progestogens have remained obscure, and incompatible with the antiproliferative action shown by activation of the progesterone receptor (PR) in the endometrium. The receptor activator of nuclear factor kappa B (RANK), and its ligand, RANKL, are members of the tumor necrosis factor (TNF) superfamily of cytokines. The RANKL/RANK system participates in several functions in the body, involving among others the immunological system and osteoclast differentiation in bone marrow progenitors [7]. A series of studies in rodents have shown that RANKL/RANK are essential for the development of lobulo-alveolar mammary structures, and that silencing the RANK gene in knockout mice is associated with defective proliferation and increased apoptosis of mammary cells [8]. Along the same lines, animal models overexpressing RANK and RANKL showed increased epithelial proliferation [9]. Evidence rapidly emerged that progesterone binding to the PR in the breast luminal epithelium is followed by both direct proliferation of those cells and increased RANKL synthesis. This cytokine behaves as a proliferative agent for neighboring cells lacking PR. Hence, a double effect is observed, with direct proliferative action on PR-expressing cells, and paracrine action mediated by synthesized RANKL in adjacent cells without PR expression [10]. The increased proliferation rate of epithelial cells paves the way for progression to in situ and invasive cancer in under favorable conditions such as the presence of a carcinogen or genetic lesion. This mechanism, already reviewed in the journal [11], is crucial to understanding progestogen-mediated carcinogenesis. In a more provocative series of experiments, RANKL has been shown to stimulate the migratory potential of malignant cells in rodents [12]. Thus, RANKL has also emerged as a potential determinant of the metastatic potential of tumors. Nonetheless, whether this mechanism observed in the breast is reproduced in the endometrium is unknown. Endometrial cancer is also hormone dependent, but the proliferative stimulus is currently linked to estrogens. As a first step, it is important to determine whether RANK is expressed in the endometrium, and whether, as shown in the breast, it may serve as a prognostic indicator in endometrial cancer. More recently published findings have confirmed both premises, including increased RANK expression in parallel to tumor dedifferentiation [13]. Moreover, another study has shown that RANK expression increases in endometriosis, as an intermediate state between normal and malignant endometrium [14]. Interesting challenges ahead include uncovering the potential role of RANK/RANKL in estrogen-dependent proliferation in the endometrium, and determining whether the progestogenic effect, which limits proliferation in the endometrium, is in any way related to the RANK/RANKL system. If this is found to be the case, unraveling the reasons this system operates in opposite ways in the breast and in the endometrium will be an inspiring area of research. And finally, from a wider perspective, it would be intriguing to clarify whether the RANK/RANKL system has some type of role in the potential promitotic action of hormones in other regions, in which regard the ovary is an exciting area [15]. Alongside their value as prognostic indicators, the use of system modulators such as the monoclonal antibody denosumab may offer therapeutic advantages worth exploring in clinical trials.