Mediterranean diet for cancer prevention and survivorship.

Cancer is one of the main noncommunicable diseases in terms of health impact. Factors such as a progressively aging population point to future increases in the incidence of cancer on a global level. The elevated number of affected individuals, together with continuous improvements in cancer prevention and therapy, is creating a growing population of cancer survivors, with often inadequately met needs. Lifestyle is a key modulator of cancer risk and of associated morbidity and mortality, and is included in all approaches to the long-term management of cancer. Diet is a principal component of lifestyle, and most of the available evidence is centered on the Mediterranean diet. Our objective was to provide a narrative review of the evidence on the effect of the Mediterranean diet on cancer risk and health threats related to cancer survivorship. For this purpose, we searched the PubMed database for articles published between January 1, 2000, and June 12, 2023. Current data show that the Mediterranean diet is inversely associated with risk, or is risk neutral, for most types of cancer. Tumors of the digestive system have received preferential interest, but studies have also been published on tumors in other organs. The evidence, however, is meager due to the observational nature of most studies, although it is reassuring that benefit is reproduced in studies performed in different populations and environments. Evidence related to cancer survivors is limited by the paucity of studies, yet several findings regarding survival, recurrence, and short- and long-term morbidity suggest a potential role for the Mediterranean diet that warrants further research.

Both reduced ovarian reserve and severe semen alterations are overrepresented in couples seeking assisted reproductive technology treatment for the first time: a cross-sectional study.

BACKGROUND: Once a mate choice decision has been made, couples that fail to reach a live birth in natural and/or intrauterine insemination (IUI) cycles will likely visit fertility clinics seeking assisted reproductive technology (ART) treatment. During the more or less prolonged period of infertility experienced, those couples with mild/moderate reproductive anomalies would have advantage over couples displaying more severe reproductive alterations in achieving a natural or IUI conception. Thus, we can expect to find a progressive increase in the proportion of couples with more severe reproductive anomalies as duration of infertility rises. In this study, we aim to ascertain whether there is an association between male and female infertility diagnoses and duration of infertility in couples seeking ART treatment for the first time. METHODS: A cross-sectional analysis of 1383 infertile couples that sought ART treatment for the first time. Forward-stepwise binary logistic regression analyses were applied to calculate exponentiated regression coefficients. RESULTS: Men suffering from any combination of oligo-, astheno-, and teratozoospermia (ACOAT) exhibited higher odds of having a duration of infertility > 2 years compared with non-ACOAT men [odds ratio (95% confidence interval): 1.340 (1.030-1.744)]. Women from ACOAT couples displaying a duration of infertility > 2 years presented shorter menstrual cycles (P ≤ 0.047) and lower antral follicular count (AFC) values (P ≤ 0.008) and serum anti-Müllerian hormone (AMH) levels (P ≤ 0.007) than women from non-ACOAT couples exhibiting > 2 years of infertility. Likewise, AFC values (P ≤ 0.013) and serum AMH levels (P ≤ 0.001) were decreased when compared with women from ACOAT couples displaying ≤ 2 years of infertility. A relative low but significant percentage of ACOAT couples displaying > 2 years of infertility stood out for their smoking habits. CONCLUSIONS: Couples consisting of ACOAT men and women with a relative low ovarian reserve are overrepresented in couples seeking ART treatment for the first time after experiencing > 2 years of infertility. This outcome leads us to develop a general hypothesis proposing that the origin of couple's infertility is a consequence of a process of positive assortative mating shaped by sexual selection forces.

Identification of Altered Evoked and Non-Evoked Responses in a Heterologous Mouse Model of Endometriosis-Associated Pain.

The aim of this study was to develop and refine a heterologous mouse model of endometriosis-associated pain in which non-evoked responses, more relevant to the patient experience, were evaluated. Immunodeficient female mice (N = 24) were each implanted with four endometriotic human lesions (N = 12) or control tissue fat (N = 12) on the abdominal wall using tissue glue. Evoked pain responses were measured biweekly using von Frey filaments. Non-evoked responses were recorded weekly for 8 weeks using a home cage analysis (HCA). Endpoints were distance traveled, social proximity, time spent in the center vs. outer areas of the cage, drinking, and climbing. Significant differences between groups for von Frey response, climbing, and drinking were detected on days 14, 21, and 35 post implanting surgery, respectively, and sustained for the duration of the experiment. In conclusion, a heterologous mouse model of endometriosis-associated evoked a non-evoked pain was developed to improve the relevance of preclinical models to patient experience as a platform for drug testing.

Histological Grade and Tumor Stage Are Correlated with Expression of Receptor Activator of Nuclear Factor Kappa b (Rank) in Epithelial Ovarian Cancers.

The receptor activator of nuclear factor kappa B (RANK) is becoming recognized as a master regulator of tumorigenesis, yet its role in gynecological cancers remains mostly unexplored. We investigated whether there is a gradation of RANK protein and mRNA expression in epithelial ovarian cancer (EOC) according to malignancy and tumor staging. Immunohistochemical expression of RANK was examined in a cohort of 135 (benign n = 29, borderline n= 23 and malignant n = 83) EOCs. Wild type and truncated RANK mRNA isoform quantification was performed in a cohort of 168 (benign n = 26, borderline n = 13 and malignant n = 129) EOCs. RANK protein and mRNA values were increased in malignant vs. benign or borderline conditions across serous, mucinous and endometrioid cancer subtypes. Additionally, a trend of increased RANK values with staging was observed for the mucinous and serous histotype. Thus, increased expression of RANK appears associated with the evolution of disease to the onset of malignancy in EOC. Moreover, in some EOC histotypes, RANK expression is additionally associated with clinicopathological markers of tumor aggressiveness, suggesting a role in further progression of tumor activity.

Variants translating reduced expression of the beta estrogen receptor gene were associated with increased carotid intima media thickness: A cross-sectional study in late postmenopausal women.

ABSTRACT: There is debate on the role of estrogens in modulating the risk for atherosclerosis in women. Our purpose was to investigate whether the size of the estrogenic impact was independently associated with variation of carotid intima-media thickness (IMT) in healthy late postmenopausal women. The levels of circulating estrogens have been used in previous studies but the influence of SNPs of the estrogen receptors (ER) α and ß have not been investigated.We performed a crossed-sectional study of 91 women in a university hospital. We used a double approach in which, in addition to the measurement of estradiol levels by ultrasensitive methods, genetic variants (SNPs) associated with differing expression of the ER α and ß genes were assessed. Multivariable analysis was used to examine the association of candidate factors with the value of IMT and plaque detection at both the carotid wall and the sinus.A genotype combination translating reduced gene expression of the ERß was directly associated with IMT at both the carotid wall (P = .001) and the sinus (P = .002). Other predictors of IMT were the levels of glucose, positively associated with IMT at both the carotid wall (P < .001) and the sinus (P = .001), age positively associated with IMT at the sinus (P = .003), and levels of vitamin D, positively associated with IMT at the carotid wall (P = .04).Poorer estrogenic impact, as concordant with a SNP variant imposing reduced expression of the ERß, was directly associated with IMT at both the carotid wall and the sinus. Glucose level, vitamin D only for the carotid wall, and age only for the sinus, also emerged as independent factors in the IMT variance.

A Reassessment of the Therapeutic Potential of a Dopamine Receptor 2 Agonist (D2-AG) in Endometriosis by Comparison against a Standardized Antiangiogenic Treatment.

Dopamine receptor 2 agonists (D2-ags) have been shown to reduce the size of tumors by targeting aberrant angiogenesis in pathological tissue. Because of this, the use of a D2-ag was inferred for endometriosis treatment. When assayed in mouse models however, D2-ags have been shown to cause a shift of the immature vessels towards a more mature phenotype but not a significant reduction in the amount of vascularization and size of lesions. These has raised concerns on whether the antiangiogenic effects of these compounds confer a therapeutic value for endometriosis. In the belief that antiangiogenic effects of D2-ags in endometriosis were masked due to non-optimal timing of pharmacological interventions, herein we aimed to reassess the antiangiogenic therapeutic potential of D2-ags in vivo by administering compounds at a timeframe in which vessels in the lesions are expected to be more sensitive to antiangiogenic stimuli. To prove our point, immunodeficient (NU/NU) mice were given a D2-ag (cabergoline), anti-VEGF (CBO-P11) or vehicle (saline) compounds (n = 8 per group) starting 5 days after implantation of a fluorescently labeled human lesion. The effects on the size of the implants was estimated by monitoring the extent of fluorescence emitted by the lesion during the three-week treatment period. Subsequently mice were sacrificed and lesions excised and fixed for quantitative immunohistochemical/immunofluorescent analysis of angiogenic parameters. Lesion size, vascular density and innervation were comparable in D2-ag and anti-VEGF groups and significantly decreased when compared to control. These data suggest that D2-ags are as powerful as standard antiangiogenic compounds in interfering with angiogenesis and lesion size. Our preliminary study opens the way to further exploration of the mechanisms beneath the antiangiogenic effects of D2-ags for endometriosis treatment in humans.

Bazedoxifene increases the proliferation of human arterial endothelial cells but does not affect the expression of cyclins A, B, and D1 and of p27Kip1.

OBJECTIVE: Endothelial dysfunction and denudation are considered a first step in atherosclerosis. Endothelial proliferation is key for cellular repair. The effect of bazedoxifene on the vascular endothelium has not been explored. We investigated the effect of bazedoxifene on endothelial cell proliferation. METHODS: Primary cultures from human umbilical artery endothelial cells were used in dose-response experiments (0.1, 1.0, and 10.0 EC50 dose) with bazedoxifene, estradiol, raloxifene and a combination of bazedoxifene and estradiol. Proliferation was assessed with the XTT colorimetric cell-proliferation assay. The possible participation of cyclins A, B, D1 and p27Kip1 was analyzed by the measurement of their expression at both the protein and the gene levels. RESULTS: A significant increase of similar size for cell proliferation was obtained with bazedoxifene, estradiol and raloxifene, but no significant change was observed for the association of bazedoxifene and estradiol. The impact was detected at the first 0.1 EC50 dose and was not dose-dependent. Estradiol achieved a significant increase in the protein expression of cyclin A and p27Kip1, but no change was detected for the other compounds at either the gene or protein level. CONCLUSION: Bazedoxifene demonstrated a proliferative effect of similar size to estradiol in cultured human umbilical artery endothelial cells. The molecular mechanisms need further investigation.

Comparative transcriptome analysis identifies CARM1 and DNMT3A as genes associated with osteoporosis.

To identify new candidate genes in osteoporosis, mainly involved in epigenetic mechanisms, we compared whole gene-expression in osteoblasts (OBs) obtained from women undergoing hip replacement surgery due to fragility fracture and severe osteoarthritis. Then, we analyzed the association of several SNPs with BMD in 1028 women. Microarray analysis yielded 2542 differentially expressed transcripts belonging to 1798 annotated genes, of which 45.6% (819) were overexpressed, and 54.4% (979) underexpressed (fold-change between - 7.45 and 4.0). Among the most represented pathways indicated by transcriptome analysis were chondrocyte development, positive regulation of bone mineralization, BMP signaling pathway, skeletal system development and Wnt signaling pathway. In the translational stage we genotyped 4 SNPs in DOT1L, HEY2, CARM1 and DNMT3A genes. Raw data analyzed against inheritance patterns showed a statistically significant association between a SNP of DNMT3A and femoral neck-(FN) sBMD and primarily a SNP of CARM1 was correlated with both FN and lumbar spine-(LS) sBMD. Most of these associations remained statistically significant after adjusting for confounders. In analysis with anthropometric and clinical variables, the SNP of CARM1 unexpectedly revealed a close association with BMI (p = 0.000082), insulin (p = 0.000085), and HOMA-IR (p = 0.000078). In conclusion, SNPs of the DNMT3A and CARM1 genes are associated with BMD, in the latter case probably owing to a strong correlation with obesity and fasting insulin levels.

Diet to Reduce the Metabolic Syndrome Associated with Menopause. The Logic for Olive Oil.

The rates of metabolic syndrome are increasing in parallel with the increasing prevalence of obesity, primarily due to its concomitant insulin resistance. This is particularly concerning for women, as the years around menopause are accompanied by an increase in visceral obesity, a strong determinant of insulin resistance. A fall in estrogens and increase in the androgen/estrogen ratio is attributed a determining role in this process, which has been confirmed in other physiological models, such as polycystic ovary syndrome. A healthy lifestyle, with special emphasis on nutrition, has been recommended as a first-line strategy in consensuses and guidelines. A consistent body of evidence has accumulated suggesting that the Mediterranean diet, with olive oil as a vital component, has both health benefits and acceptable adherence. Herein, we provide an updated overview of current knowledge on the benefits of olive oil most relevant to menopause-associated metabolic syndrome, including an analysis of the components with the greatest health impact, their effect on basic mechanisms of disease, and the state of the art regarding their action on the main features of metabolic syndrome.

Association of a single nucleotide polymorphism of RANK gene with blood pressure in Spanish women.

In addition to governing key functions in bone metabolism and the immune system, the RANK/RANKL/OPG system plays a role in the vascular system, particularly in vascular calcification and atherosclerosis.Given that these 2 phenotypes are considered a major cause of high blood pressure (BP), in this study we analyzed the association of SNPs in RANK and OPG genes with blood pressure. An observational study was conducted of 2 SNPs in the RANK gene (rs884205 and rs78326403) and 1 in the OPG gene (rs4876869) with systolic (SBP) and diastolic blood pressure (DBP) in a cohort of 695 women.Data analysis revealed a statistically significant association between the SNP rs884205 and BP pressure (SBP and DBP). Analyzing this relationship by the dominant inheritance model for this SNP (allele risk: A), women of the AA/AC genotype showed higher BP than women of the CC genotype, both for SBP (P = .001) and for DBP (P = .003), and these associations both surpassed the Bonferroni threshold for multiple comparisons. Multivariate regression analysis including known predictors of BP as independent variables was performed to evaluate the strength of this association, which in the case of the SNP rs884205 of the RANK gene remained statistically significant after adjustment for both SBP (P = .0006) and DBP (P = .005), demonstrating the key role of this SNP in BP.We report a robust association between the SNP rs884205 in RANK gene and BP in women, and this SNP is validated as a candidate in cardiovascular risk studies.

A predictive model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle.

PURPOSE: To introduce a prognostic model for women's assisted fecundity before starting the first IVF/ICSI treatment cycle. METHODS: In contrast to previous predictive models, we analyze two groups of women at the extremes of prognosis. Specifically, 708 infertile women that had either a live birth (LB) event in the first autologous IVF/ICSI cycle ("high-assisted-fecundity women", n = 458) or did not succeed in having a LB event after completing three autologous IVF/ICSI cycles ("low-assisted-fecundity women", n = 250). The initial sample of 708 women was split into two sets in order to develop (n = 531) and internally validate (n = 177) a predictive logistic regression model using a forward-stepwise variable selection. RESULTS: Seven out of 32 initially selected potential predictors were included into the model: women's age, presence of multiple female infertility factors, number of antral follicles, women's tobacco smoking, occurrence of irregular menstrual cycles, and basal levels of prolactin and LH. The value of the c-statistic was 0.718 (asymptotic 95% CI 0.672-0.763) in the development set and 0.649 (asymptotic 95% CI: 0.560-0.738) in the validation set. The model adequately fitted the data with no significant over or underestimation of predictor effects. CONCLUSION: Women's assisted fecundity may be predicted using a relatively small number of predictors. This approach may complement the traditional procedure of estimating cumulative and cycle-specific probabilities of LB across multiple complete IVF/ICSI cycles. In addition, it provides an easy-to-apply methodology for fertility clinics to develop and actualize their own predictive models.

Receptor Activator of Nuclear Factor Kappa B (RANK) and Clinicopathological Variables in Endometrial Cancer: A Study at Protein and Gene Level.

The system integrated by the receptor activator of nuclear factor kappa B (RANK) and its ligand, RANKL, modulates the role of hormones in the genesis and progression of breast tumors. We investigated whether the expression of RANK was related with clinicopathological features of primary endometrial tumors. Immunohistochemistry was used in an endometrial cancer tissue array containing samples from 36 tumors. The amount of RANK mRNA was examined in a tissue scan cDNA array containing cDNA from 40 tumors. Normal endometrium was examined for comparison. Immunohistochemical analyses showed that RANK expression was higher in malignant than in normal endometrium (p < 0.05). RANK expression was related to histological grade (Pearson correlation index = 0.484, p < 0.001), but not to tumor stage or to age of the women. The gene expression was similar in malignant and normal endometrium. The study of RANK isoforms confirmed that the overall relative abundance of the three clearly identified transcripts was similar in normal and pathological endometrium. RANK protein expression increased from normal to malignant endometrium, and the expression level was related with tumor grade but not with stage or the age of subjects in endometrial cancer. In contrast, similar comparisons showed no change in RANK gene expression.

Hormonal contraceptives and breast cancer: Clinical data.

The endocrine background of breast cancer has raised questions about the increase in risk that might bear the use of hormonal contraceptives. This has been a particular issue in the case of young women, who constitute the population of contraceptive consumers. Observational studies have been the main source of evidence, which has mainly limited to the combined estrogen-progestogen preparations, the popular pill. Studies in the 80's and 90's of the past century found a small, around a 20%, increase in risk. The translation in absolute number of excess cases has been exiguous because the prevalence of the disease is relatively small in premenopausal women. Moreover, the risk slowly seemed to disappear after 5-10 years of use. The more sophisticated analyses provided by new technologies, together with the powerful central registries in some countries, has confirmed increased risk of similar size. Recent preparations, with lower doses of estrogens and new progestogenic molecules, have not substantially modified the risk size. The impact of progestogen only alternatives, either pills or progestogen-loaded intrauterine devices, seems to be similar, but the evidence is still insufficient. Whether there is a preferential effect on histological or molecular subtypes of breast tumours is being debated yet. The data on women at higher risk, either with mutations of the BRCA1/2 genes or with familial weight, have not found specific response patterns, but the experience is still meagre. It is of interest that long-term follow up data on women who enrolled in the initial cohorts, like that of the Royal College of General Practitioners', have shown a considerable protection against cancer of the ovary (relative risk, RR 0.67), endometrium (RR 0.66), or colorectum (RR 0.81).

The action of estrogens and progestogens in the young female breast.

Evidence from different sources sustains a pro-oncogenic role of hormones, estrogens and progestogens, on the breast. The issue is of interest for young women, who are exposed to the hormonal changes imposed by the ovarian cycle and, often, take hormones with contraceptive purposes. Experimental and clinical studies show that both estrogens and progesterone are involved in mammary development during puberty and lactation, the changes being observed across mammalian species, including humans. Estrogen receptors, and more particularly the alpha isoform, participate in molecular processes of stem cells differentiation and epithelial proliferation through paracrine actions implicating growth factors. Progesterone also contributes through paracrine mechanisms involving one member of the tumor necrosis factor (TNF) family, the receptor activator of nuclear factor κB ligand (RANKL) and its receptor (RANK). Epidemiological studies have found that the length of the exposure to endogenous hormones, as determined by an early menarche or a late menopause, is a risk factor for breast cancer. Additional evidence has derived from studies with compounds modulating the estrogen or the progesterone receptors. Selective estrogen receptor modulators (SERM), like tamoxifen, have been shown to decrease the risk of breast cancer in both pre- and post-menopausal women. Aromatase inhibitors, which drastically reduce the levels of circulating estrogens, have reproduced the findings. The selective progesterone receptor modulators (SPRM) have been less investigated and issues concerning safety have arisen. These observations have interest for young women. High-risk women may consider the use of SERMs, for example, to reduce their risk. Much more common is the case of women who take hormones for contraception. The goal of the present article is twofold: i) to summarize the actual knowledge of the mechanisms implicating estrogens and progestogens on the risk for breast cancer and ii) to provide rationality for the debate about potential cancer risk of hormonal contraceptives, frequently used by premenopausal women.

Effectiveness and quality of life 10 years after transobturator suburethral tape surgery for stress urinary incontinence.

AIM: We aimed to measure the effectiveness and quality of life (QoL) 10 years after transobturator suburethral tape surgery. METHODS: We carried out a prospective observational study of 42 women assessed 10 years after surgical intervention with the transobturator technique. The main outcome measures were subjective and objective cure or improvement, complications, and changes in QoL. RESULTS: The median abdominal leak point pressure had been 92 (82-113) mL H2 O prior to surgery. Thirty-six women (85.7%) remained cured (negative cough test) and 13 (31%) reported urine leakage during physical activity, percentages which were similar to those at a previous assessment at the 5th year. Urgency urinary incontinence was reported by 18 women (42.9%), 16 of whom required the use of anticholinergic drugs. Nineteen women had undergone some form of surgical pelvic reconstruction concomitantly with the TOT procedure, four of whom presented with relapse. The QoL tests indicated that cure and improvement persisted in 85.7% (n = 36, Urogenital Distress Inventory-6) and 92.9% (n = 39, Incontinence Impact Questionnaire-7) of the 42 evaluable women, respectively. CONCLUSION: Rates of objective and subjective effectiveness remained stable after 10 years of surgery and QoL did not deteriorate significantly during that interval. The increase in urgency incontinence needs to be further investigated.

Obstetric and offspring risks of women's morbid conditions linked to prior anticancer treatments.

BACKGROUND: Literature shows the effects of type of cancer and/or anticancer treatment on live birth percentages and/or pregnancy and neonatal complications in female cancer survivors. However, studies analyzing the obstetric and offspring risks of the morbid conditions associated with previous anti-cancer treatments are missing. The present review aims to uncover these risks. METHODS: A literature search based on publications up to March 2016 identified by PubMed and references cited in relevant articles. RESULTS: The morbid conditions associated with prior anticancer treatments including chemotherapy, radiotherapy, surgery, and/or hematopoietic stem-cell transplant may induce not only obstetric and neonatal complications but also long-term effects on offspring. Whereas some risks are predominantly evidenced in untreated women others are observed in both treated and untreated women. These risks may be superimposed on those induced by the current women's trend in Western societies to postpone maternity. CONCLUSIONS: Medical professionals should be aware and inform female cancer survivors wishing to have a child not only of the short- and long-term risks to themselves and their prospective offspring of previous anticancer treatments, fertility-preservation technologies, and pregnancy itself, but also of those risks linked to the morbid conditions induced by prior anticancer treatments. Once female cancer survivors wishing to have a child have been properly informed about the risks of reproduction, they will be best placed to make decisions of whether or not to have a biological or donor-conceived child. In addition, when medical professionals be aware of these risks, they will be also best placed to provide appropriate treatments before/during pregnancy in order to prevent or alleviate the impact of these morbid conditions on maternal and offspring health.

The role of CD40 and CD40L in bone mineral density and in osteoporosis risk: A genetic and functional study.

Compelling data are revealing that the CD40/CD40L system is involved in bone metabolism. Furthermore, we have previously demonstrated that polymorphisms in both genes are associated with bone phenotypes. The aim of this study is to further characterize this association and to identify the causal functional mechanism. We conducted an association study of BMD with 15 SNPs in CD40/CD40L genes in a population of 779 women. In addition, we assessed the functionality of this association through the study of the allele-dependent expression of CD40 and CD40L in peripheral blood leukocytes (PBLs) and in human osteoblasts (OBs) obtained from bone explants by qPCR and by sequencing. When an allelic imbalance (AI) was detected, studies on allele-dependent in vitro transcription rate and on CpG methylation in the gene promoter were also performed. Our results confirm the genetic association between SNP rs116535 (T>C) of CD40L gene with LS-BMD. Regarding CD40 gene, two SNPs showed nominal P-values<0.05 for FN- and LS-BMD (Z-scores), although the association was not significant after correcting for multiple testing. Homozygous TT women for SNP rs1883832 (C>T) of CD40 gene showed a trend to have lower levels of OPG (Q-value=0.059), especially when women of BMD-quartile ends were selected (P<0.05). Regarding functionality, we detected an AI for rs1883832 with the C allele the most expressed in OBs and in PBLs. Since the rs116535 of CD40L gene did not show AI, it was not further analyzed. Finally, we described a differential methylation of CpGs in the CD40 promoter among women of high in comparison to low BMD. Our results suggest that the CD40/CD40L system plays a role in regulating BMD. Effectively, our data suggest that a decreased production of OPG could be the cause of the lower BMD observed in TT women for rs1883832 of the CD40 gene and that the degree of methylation of CpGs in the CD40 promoter could contribute to the acquisition of BMD. One possibility that deserves further study is whether the degree of methylation of the CD40 gene affects the level of CD40 expression and, consequently, the level of OPG.

Progestogens and risk of breast cancer: a link between bone and breast?

This article reviews the data supporting the role of receptor activator of the nuclear factor kappa (RANK) and its ligand, RANKL, in progestogen-induced breast cancer. Both experimental and clinical studies have been included. The expression of both RANK and RANKL has been described in epithelial cells of both mice and humans. Experiments of gain and loss of function in mice have shown that RANK/RANKL mediate alveologenesis during pregnancy or the estrous cycle. Moreover, the participation of the RANK/RANKL has been detected in models of breast carcinogenesis associated with progestogens-like medroxyprogesterone acetate. Recent clinical studies have found that the expression of RANK is associated with parameters of aggressiveness of the tumor.