Hormone-Dependent Tumors and Sexuality in the Neuro-Oncology of Women (N.O.W.): Women's Brain Tumors, Gaps in Sexuality Considerations, and a Need for Evidence-Based Guidelines.

PURPOSE OF REVIEW: While females make up almost 60% of all brain and spinal cord tumors in adults, guidelines that address women's issues in neuro-oncology are lacking. This review sheds light on two common women's issues in neuro-oncology. RECENT FINDINGS: Neuro-oncology providers are often faced with patient questions about fertility and pregnancy maintenance or prevention and typically respond with generic cancer chemotherapy recommendations, based on the paucity of evidence on the use of common neuro-oncology chemotherapies and pregnancy. While these remain important gap issues, there are several other poorly researched issues in the Neuro-Oncology of Women (N.O.W.) including recommendations around endogenous and iatrogenic hormone exposure and female sexuality in cancer. As a significant percentage of cancers are hormone-dependent, it is important to understand how changes in hormone levels impact tumor biology over the course of a woman's lifespan. Furthermore, greater attention should be given to the impact of tumors and tumor treatments on female sexuality. This article is intended to serve as an introduction to these two specific subjects within the vast expanse of N.O.W. subject matter.

Targeting obesity-related dysfunction in hormonally driven cancers.

Obesity is a risk factor for at least 13 different types of cancer, many of which are hormonally driven, and is associated with increased cancer incidence and morbidity. Adult obesity rates are steadily increasing and a subsequent increase in cancer burden is anticipated. Obesity-related dysfunction can contribute to cancer pathogenesis and treatment resistance through various mechanisms, including those mediated by insulin, leptin, adipokine, and aromatase signalling pathways, particularly in women. Furthermore, adiposity-related changes can influence tumour vascularity and inflammation in the tumour microenvironment, which can support tumour development and growth. Trials investigating non-pharmacological approaches to target the mechanisms driving obesity-mediated cancer pathogenesis are emerging and are necessary to better appreciate the interplay between malignancy, adiposity, diet and exercise. Diet, exercise and bariatric surgery are potential strategies to reverse the cancer-promoting effects of obesity; trials of these interventions should be conducted in a scientifically rigorous manner with dose escalation and appropriate selection of tumour phenotypes and have cancer-related clinical and mechanistic endpoints. We are only beginning to understand the mechanisms by which obesity effects cell signalling and systemic factors that contribute to oncogenesis. As the rates of obesity and cancer increase, we must promote the development of non-pharmacological lifestyle trials for the treatment and prevention of malignancy.

Heparanase Accelerates Obesity-Associated Breast Cancer Progression.

Obese women have higher risk of bearing breast tumors that are highly aggressive and resistant to therapies. Tumor-promoting effects of obesity occur locally via adipose inflammation and related alterations to the extracellular matrix (ECM) as well as systemically via circulating metabolic mediators (e.g., free fatty acids, FFA) associated with excess adiposity and implicated in toll-like receptor-mediated activation of macrophages-key cellular players in obesity-related cancer progression. Although the contribution of macrophages to proneoplastic effects of obesity is well documented, the role of ECM components and their enzymatic degradation is less appreciated. We show that heparanase, the sole mammalian endoglucuronidase that cleaves heparan sulfate in ECM, is preferentially expressed in clinical/experimental obesity-associated breast tumors. Heparanase deficiency abolished obesity-accelerated tumor progression in vivo. Heparanase orchestrated a complex molecular program that occurred concurrently in adipose and tumor tissue and sustained the cancer-promoting action of obesity. Heparanase was required for adipose tissue macrophages to produce inflammatory mediators responsible for local induction of aromatase, a rate-limiting enzyme in estrogen biosynthesis. Estrogen upregulated heparanase in hormone-responsive breast tumors. In subsequent stages, elevated levels of heparanase induced acquisition of procancerous phenotype by tumor-associated macrophages, resulting in activation of tumor-promoting signaling and acceleration of breast tumor growth under obese conditions. As techniques to screen for heparanase expression in tumors become available, these findings provide rational and a mechanistic basis for designing antiheparanase approaches to uncouple obesity and breast cancer in a rapidly growing population of obese patients. SIGNIFICANCE: This study reveals the role of heparanase in promoting obesity-associated breast cancer and provides a mechanistically informed approach to uncouple obesity and breast cancer in a rapidly growing population of obese patients.

Gender-affirming hormone therapy and the risk of sex hormone-dependent tumours in transgender individuals-A systematic review.

BACKGROUND: Cancers are a leading cause of death worldwide, and transgender individuals are no exception. The effects of gender-affirming hormone therapy (GAHT) on sex hormone-dependent tumours are unclear. Therefore, this review seeks to determine whether tumour risk in transgender individuals differs from the general population, to guide clinical screening recommendations. METHODS: We performed a systematic review based on the PRISMA guidelines. MEDLINE, Embase and PsycINFO databases were searched for studies examining tumour incidence, prevalence or cancer-related mortality in transgender individuals. All English peer-reviewed publications were included if histological type and temporal relation to GAHT were reported. Case reports were included if there were ≥2 cases of the same histological type. RESULTS: The search strategy identified 307 studies. Excluding those that did not meet inclusion criteria, 43 studies (7 cohort studies, 2 cross-sectional studies and 34 case reports) were reviewed. Retrospective cohort studies suggest no increase in risk of tumour development in transgender individuals receiving GAHT compared to the general population. Notably, the mean ages of cohorts were young and were treated with GAHT for insufficient durations to assess tumour risk. Case reports raise potential associations between high-dose oestradiol and anti-androgen therapy with prolactinoma and meningioma, respectively. CONCLUSIONS: Further longitudinal studies are required to assess the risk of GAHT and hormone-dependent tumour development. Until further evidence is available, tumour screening should be based on guidelines for the general population and the presence of organs in transgender individuals rather than gender identity or hormonal therapy status.

Obesity surgery and risk of cancer.

BACKGROUND: Obesity increases the risk of several types of cancer. Whether bariatric surgery influences the risk of obesity-related cancer is not clear. This study aimed to uncover the risk of hormone-related (breast, endometrial and prostate), colorectal and oesophageal cancers following obesity surgery. METHODS: This national population-based cohort study used data from the Hospital Episode Statistics database in England collected between 1997 and 2012. Propensity matching on sex, age, co-morbidity and duration of follow-up was used to compare cancer risk among obese individuals undergoing bariatric surgery (gastric bypass, gastric banding or sleeve gastrectomy) and obese individuals not undergoing such surgery. Conditional logistic regression provided odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: In the study period, from a cohort of 716 960 patients diagnosed with obesity, 8794 patients who underwent bariatric surgery were matched exactly with 8794 obese patients who did not have surgery. Compared with the no-surgery group, patients who had bariatric surgery exhibited a decreased risk of hormone-related cancers (OR 0·23, 95 per cent c.i. 0·18 to 0·30). This decrease was consistent for breast (OR 0·25, 0·19 to 0·33), endometrium (OR 0·21, 0·13 to 0·35) and prostate (OR 0·37, 0·17 to 0·76) cancer. Gastric bypass resulted in the largest risk reduction for hormone-related cancers (OR 0·16, 0·11 to 0·24). Gastric bypass, but not gastric banding or sleeve gastrectomy, was associated with an increased risk of colorectal cancer (OR 2·63, 1·17 to 5·95). Longer follow-up after bariatric surgery strengthened these diverging associations. CONCLUSION: Bariatric surgery is associated with decreased risk of hormone-related cancers, whereas gastric bypass might increase the risk of colorectal cancer.

[Endocrinology of cancer and age: early and late stages of ontogenesis].

Processes important for hormone-mediated carcinogenesis are present on different, even very early, ontogenesis stages. Early shifts in hormone-metabolic status often display opposite correlations with the risk of most common age-associated non-communicable pathologies (namely, hormone-dependent cancers and cardiovascular diseases). Additional known contradiction is the raise of reproductive system tumors incidence in the age associated with lower production of mitogenic hormones. Consequently, one should take into account production of steroids in target tissues themselves, recognize the importance of progenotoxic effect, which, apart from mitogenic function, is characteristic for estrogens and their derivatives, as well as the role of endocrine-genotoxic switchings forming so called basic triad, which is born under the influence of age-associated endocrine shifts and environmental factors. Aside from steroids-related system of increased cancer risk, attention should be paid to non-steroid ones (in particular insulin resistance- and inflammatory cytokines-associated), with their close connection to immune system functional state, low-grade chronic inflammation, obesity phenotype, and pro-/anti-inflammatory lipid factors ratio. In total, it confirms and importance of timely preventive interventions on both ontogenesis stages, early and late ones, which are often separated by several decades.

The testosterone conundrum: The putative relationship between testosterone levels and prostate cancer.

BACKGROUND: The controversy surrounding the relationship between testosterone and prostate cancer has existed for decades. The literature surrounding this topic is confusing and at times contradictory. There is no level-one quality evidence that confirms or refutes the relationship between either high or low serum testosterone levels and the subsequent development of prostate cancer. This commentary aims to review the issues involved and to provide an interpretation as to the causes of the confusion and to provide a framework for ongoing discussion and investigation. MATERIALS AND METHODS: A Medline and PubMed search was conducted using search terms: testosterone levels and prostate cancer to identify pertinent literature. RESULTS: There is no consistent evidence that a single testosterone level is predictive of prostate cancer risk. CONCLUSION: The development of prostate cancer is a complex biologic process potentially involving genetics,dietary, life style and hormonal factors. Serum testosterone levels do not accurately reflect the internal prostatic milieu. Finally, if testosterone levels are to be considered in the etiology of prostate cancer they should be measured and interpreted on a chronic basis with multiple measurements over a period of years.

Conditional Expression of the Androgen Receptor Increases Susceptibility of Bladder Cancer in Mice.

Bladder cancer represents a significant human tumor burden, accounting for about 7.7% and 2.4% of all cancer cases in males and females, respectively. While men have a higher risk of developing bladder cancer, women tend to present at a later stage of disease and with more aggressive tumors. Previous studies have suggested a promotional role of androgen signaling in enhancing bladder cancer development. To directly assess the role of androgens in bladder tumorigenesis, we have developed a novel transgenic mouse strain, R26hARLoxP/+:Upk3aGCE/+, in which the human AR transgene is conditionally expressed in bladder urothelium. Intriguingly, both male and female R26hARLoxP/+:Upk3aGCE/+ mice display a higher incidence of urothelial cell carcinoma (UCC) than the age and sex matched control littermates in response to the carcinogen, N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN). We detect expression of the human AR transgene in CK5-positive and p63-positive basal cells in bladder urothelium. Further analyses of UCC tissues from R26hARLoxP/+:Upk3aGCE/+ mice showed that the majority of tumor cells are of urothelial basal cell origin. Positive immunostaining of transgenic AR protein was observed in the majority of tumor cells of the transgenic mice, providing a link between transgenic AR expression and oncogenic transformation. We observed an increase in Ki67 positive cells within the UCC lesions of transgenic AR mice. Manipulating endogenous androgen levels by castration and androgen supplementation directly affected bladder tumor development in male and female R26hARLoxP/+:Upk3aGCE/+ mice, respectively. Taken together, our data demonstrate for the first time that conditional activation of transgenic AR expression in bladder urothelium enhances carciongen-induced bladder tumor formation in mice. This new AR transgenic mouse line mimics certain features of human bladder cancer and can be used to study bladder tumorigenesis and for drug development.

Obesity and cancer: mechanistic insights from transdisciplinary studies.

Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie-restriction studies in mouse models that support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link.

[MALIGNANT MELANOMA--THE INFLUENCE OF HORMONAL FACTORS ON THE PROGRESSION AND PROGNOSIS. COMPARATIVE ANALYSIS BASED ON TWO CLINICAL CASES].

Malignant melanoma is the most aggressive form of skin cancer showing extremely high metastatic rate and leading to high levels of lethality. The continually growing incidence of malignant melanoma in the world and his difficult early diagnosis are the occasion for numerous studies. The individual risk for malignant transformation of melanocytes is determined by a number of etiologic factors--endogenous and exogenous. Ultraviolet radiation has a leading role in the group of exogenous factors. Within the group of endogenous factors, besides the well-known photo type skin, as well as genes mutations, are added and the sex hormones, with their significant prognostic importance. The differences, which are observed in the progression and prognosis of malignant melanoma in pre- and postmenopausal women, and men, have defined this cutaneous neoplasma as hormone-dependent tumor. We present two seemingly similar clinical cases of 52 year old woman and 53-year-old man diagnosed with malignant melanomas, developed on the basis of pigmented lesions located on the upper back, as we attempt a comparative analysis on etiopathogenetic factors led to radically different course and prognosis of the disease in these two patients.

Defining molecular sensors to assess long-term effects of pesticides on carcinogenesis.

The abundance of dioxins and dioxin-like pollutants has massively increased in the environment due to human activity. These chemicals are particularly persistent and accumulate in the food chain, which raises major concerns regarding long-term exposure to human health. Most dioxin-like pollutants activate the aryl hydrocarbon receptor (AhR) transcription factor, which regulates xenobiotic metabolism enzymes that belong to the cytochrome P450 1A family (that includes CYP1A1 and CYP1B1). Importantly, a crosstalk exists between estrogen receptor α (ERα) and AhR. More specifically, ERα represses the expression of the CYP1A1 gene, which encodes an enzyme that converts 17ß-estradiol into 2-hydroxyestradiol. However, (ERα) does not repress the CYP1B1 gene, which encodes an enzyme that converts 17ß-estradiol into 4-hydroxyestradiol, one of the most genotoxic estrogen metabolites. In this review, we discuss how chronic exposure to xenobiotic chemicals, such as pesticides, might affect the expression of genes regulated by the AhR-ERα crosstalk. Here, we focus on recent advances in the understanding of molecular mechanisms that mediate this crosstalk repression, and particularly on how ERα represses the AhR target gene CYP1A1, and could subsequently promote breast cancer. Finally, we propose that genes implicated in this crosstalk could constitute important biomarkers to assess long-term effects of pesticides on human health.

An unusual case of a borderline Brenner tumor associated with bilateral serous cystadenoma and endometrial carcinoma.

Brenner tumor accounts for 1.5 to 2.5% of ovarian tumors. Nearly all are benign and 1% malignant. Less than twenty-five cases of borderline Brenner tumor have been reported worldwide. Our case is the first one related to a bilateral ovarian serous cystadenofibroma and endometrioid adenocarcinoma. This unusual case increases the limited data for borderline Brenner tumors.

High baby birth weight and risk of hormone-associated cancer in mothers: the cancer-cardiovascular disease dichotomy and its possible causes.

The idea of intrauterine or fetal factors being the cause of several prevalent noninfectious diseases in adults has recently gained the status of an axiom. One of the most thoroughly studied predictors is birth weight (BW). Although many published studies point at relations between BW and later adult morbidity or mortality, much less attention is paid to associations between baby BW and maternal morbidity. Available data suggest a sort of dichotomy in these relationships. Thus, cardiovascular risk is higher in mothers of babies with a reduced BW, while cancer risk, mainly of the breast and some other hormone-dependent cancers, is often higher among mothers of babies with a large BW (newborn macrosomia). This review addresses possible causes and endocrine mechanisms of this topic and suggests a 'particular' and 'general' solution for arising controversy. Emphasis is placed on a probable competition between chronic diseases (mainly, between female hormone-related cancer and cardiovascular pathology) within the concept of multiple causes of death. These associations should be remembered while studying the relation between offspring BW and maternal predisposition to hormone-associated cancers and other noncommunicable diseases.

Is polycystic ovary syndrome, a state of relative estrogen excess, a real risk factor for estrogen-dependant malignancies?

Polycystic ovary syndrome (PCOS) is a common endocrinopathy affecting women of fertile age. It is associated with several risk factors and long-term health consequences. Chronic anovulation combined with relative estrogen excess and consequent prolonged stimulatory effect on the endometrium can lead to the pathogenesis of hormonal dependant carcinoma. PCOS is thus traditionally reported to be associated with increased risk of endometrial, as well as breast and ovarian cancers. This article provides a critical literature review of the relationship between PCOS and the incidence of estrogen-dependant gynecological tumours, and it then discusses whether the commonly cited risk factor association can be substantiated by high quality studies which comply with the requirements of "evidence-based medicine."

Stromal epigenetic dysregulation is sufficient to initiate mouse prostate cancer via paracrine Wnt signaling.

Carcinomas most often result from the stepwise acquisition of genetic alterations within the epithelial compartment. The surrounding stroma can also play an important role in cancer initiation and progression. Given the rare frequencies of genetic events identified in cancer-associated stroma, it is likely that epigenetic changes in the tumor microenvironment could contribute to its tumor-promoting activity. We use Hmga2 (High-mobility group AT-hook 2) an epigenetic regulator, to modify prostate stromal cells, and demonstrate that perturbation of the microenvironment by stromal-specific overexpression of this chromatin remodeling protein alone is sufficient to induce dramatic hyperplasia and multifocal prostatic intraepithelial neoplasia lesions from adjacent naïve epithelial cells. Importantly, we find that this effect is predominantly mediated by increased Wnt/ß-catenin signaling. Enhancement of Hmga2-induced paracrine signaling by overexpression of androgen receptor in the stroma drives frank murine prostate adenocarcinoma in the adjacent epithelial tissues. Our findings provide compelling evidence for the critical contribution of epigenetic changes in stromal cells to multifocal tumorigenesis.

Local estrogen therapy and risk of breast cancer recurrence among hormone-treated patients: a nested case-control study.

Women with estrogen-positive breast cancers receive endocrine treatment such as tamoxifen and aromatase inhibitors (AI) for 5-10 years. An important side effect of these drugs is vaginal dryness for which local hormonal therapy (LHT) represents the most effective treatment but is theoretically contraindicated. This study aimed to assess whether the use of LHT increases the risk of breast cancer recurrence among women receiving endocrine treatment. We conducted a cohort study with nested case-control analysis using the United Kingdom General Practice Research Database (GPRD). The cohort included female patients at least 18 years of age, newly diagnosed with breast cancer who received at least one AI or tamoxifen prescription between January 1, 1998 and June 30, 2008. Cases, who were patients experiencing a breast cancer recurrence during follow-up, were each matched with up to 10 controls based on age, date of cohort entry, type of endocrine treatment received, and duration of follow-up. Conditional logistic regression was used to estimate rate ratios (RR), and 95 % confidence intervals. A total of 13,479 women were included in the study, of which 2,673 received AIs, 10,806 received tamoxifen, and 271 received LHT. Mean (SD) age at cohort entry was 63.7 (14.1) years, and mean follow-up was 3.5 (2.6) years. The crude recurrence rate 25.9 per 1,000 per year. Overall, the use of LHT was not associated with an increased risk of recurrence (RR: 0.78, 95 % CI 0.48-1.25) compared with non-use. In stratified analyses, LHT did not increase the risk of recurrence among tamoxifen-treated patients (RR: 0.83, 95 % CI 0.51-1.34), while the risk was not estimable among AI-treated patients since no patients receiving LHT experienced a recurrence. The use of LHT is not associated with an increase in breast cancer recurrence among women receiving a hormone therapy.

Luteinizing hormone, sex steroids and extracorporeal circulation - a promising link to treat retroperitoneal sarcomas. A reconsideration of cancer treatment.

Retroperitoneal sarcomas are rare and aggressive tumors with a negative prognosis as there is currently no satisfactory treatment for them. The only proven factor that can significantly increase the otherwise poor survival of sarcoma patients is the radically of resection. However, the completeness of resection is hindered by the hypervascularized nature of sarcomas and the frequent involvement of major blood vessels. In this context, we propose to operate on retroperitoneal sarcomas only with the use of extracorporeal circulation, applying vascular clamps above and below the tumor, even with short periods of hypothermic circulatory arrest in complex cases. This technique would allow the surgeon to achieve complete tumor resections, approach large blood vessels easier and perform sofisticated vascular reconstructions with no fear of hemorrhage which is fundamental to achieve a bloodless surgical field. Also, we speculate on the etiology of retroperitoneal sarcomas that appear mostly during the period of menopause/andropause. Although both estrogens and androgens have been incriminated in inducing various cancer types, including sarcomas, an endogenous estradiol cathabolyte has been shown to have anti-tumor effects. Considering that during menopause/andropause sex steroid levels actually decrease, our second working hypothesis is that the increasing follicle-stimulating hormone (FSH) and especially luteinizing hormone (LH) levels, together with the relative estrogen/androgen imbalance, may be the triggering cause. Also, a certain level of estrogens (Methoxyestradiol) may be essential in limiting tumor development and dedifferentiation. Given that extragonadal sarcomas appear to behave as endocrine tumors, a targeted hormonal therapy, together with controlled radical resections in complex cases of tumor vascular involvement, would certainly provide a strong link to both prevention and treatment of retroperitoneal sarcomas and even of cancer in general.

Endometrial carcinoma tumorigenesis and pharmacotherapy research.

Endometrial carcinoma is the common malignant tumor of the female genital tract, and its incidence is increasing. Two different clinicopathological subtypes are recognized based on epidemiology, genetic carcinogenesis and clinical behavior. Understanding and identifying molecular biology and genetics is essential to the development of novel therapies. This article reviews the current understanding of its risk factors, recent conceptions on its tumorigenesis and advances on its drug therapies.

Estrogen metabolism and risk of breast cancer in postmenopausal women.

BACKGROUND: Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. METHODS: We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. CONCLUSIONS: More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.