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  • Introduction Breast cancer is a


    Introduction Breast cancer is a highly prevalent malignancy. There are some recognized risk factors for breast cancer, like early menarche or late menopause, which increase the length of the exposure to hormones, as a result of a higher number of ovarian cycles [1]. Moreover, there is evidence supporting the link between the use of menopausal hormone therapy (MHT) and risk for breast cancer. Those observations add to the demonstrated pivotal role of ovarian hormones in crucial stages of breast development, like puberty and pregnancy, and in experimental breast tumorigenesis. The accumulation of those evidences, together with initial findings in epidemiologic studies with combined oral contraceptive (OC) users, took the Working Group of the International Agency for Research on Cancer (IARC/WHO) to state that OC are carcinogenic to humans [2]. That qualification has been maintained in a more recent document from the Agency [3]. As a sort of proof of concept, some clinical trials have shown that the down-regulation of the exposure to estrogens, either by using selective cftr channel receptors modulators (SERM) or by abrogating the production of estrogens with aromatase inhibitors (AI), relates with a reduction in the risk for breast cancer [[4], [5]]. While AI have been used with postmenopausal women, SERMs like tamoxifen have shown risk reduction potential for breast cancer also in premenopausal women. The above information defines a framework of very high interest for investigators, clinicians and users. It is not only that, when needed, the risk for breast cancer may be reduced thanks to the availability of drugs like SERMs or AI, but also that the accumulation of clinical data in the latter years is offering a more calibrated information of the real risk associated with hormones, either hormonal contraceptives or MHT. Therefore, the global message for premenopausal women, the population layer using hormonal contraceptives, is not of alarm but of hope, given the low impact of contraceptives on breast cancer incidence, the undetectable effect on mortality, and the long-term reduced risk on ovarian and endometrial cancer [6]. In order to improve the understanding of the particulars involved in the action of hormones, the sections below update the mechanisms regulating hormonal action, as well as the new modulating options offered by SERMs and selective progesterone receptor modulators (SPRM).
    Biological plausibility Both estrogens and progesterone have been demonstrated a main role in steps leading to the development and differentiation of cells from the main compartments in the mammary gland. Mouse models have shown that postnatal morphogenesis in the breast is triggered by both estrogens and progesterone [7]. The action occurs in some of the epithelial cells, which already express estrogen and progesterone receptors (ER and PR).
    Clinical studies
    Practical implications for young women
    Conclusion Research on the oncogenic mechanism of hormones has advanced dramatically in the latter years. The finding that progestogens are more powerful determinants of risk than estrogens in breast cancer has been added to advances in the molecular background. The discovery of the implication of RANKL, and its receptor RANK, has opened new research areas. As a natural extension, recent work is investigating the value of RANKL/RANK as biomarkers useful in better discerning the prognosis of breast cancer. Both survival and metastatic potential have been related with RANK expression [31], and this feature has been also confirmed in the disease affecting young women [32]. Furthermore, modulation of the RANK pathway is being actively investigated as a potential target to limit tumor aggressiveness [33]. The discovery of new molecules with potential to modulate the receptor has added consistency to the observations on the oncogenic role of estrogens and progestogens in the breast. Breast cancer keeps being a crucial issue that conditions the reluctance of many young women to use hormones for contraceptive purposes. The current information, however, is much limited to OC, the popular pill, and incipient information is being obtained on the impact of progestogen-only preparations, including both the levonorgestrel-loaded IUD and progestogen-only pills. Of much interest to reassure young, usually less than 45 years, users of hormonal contraception, clinical studies persistently report that the specific increased risk with hormonal contraceptives is very low. In absolute terms the risk limits to 1 extra breast cancer for 7690 users during 1 year [6]. Of course, such a low increased risk prevents any analysis on mortality, which most probably will be nil. The new clinical data confirming protection against ovarian and endometrial cancer in the long term should also be added in order to better support the decision of women considering the intake of hormonal contraceptives [6].