Acquired convergence of hormone signaling in breast cancer: ER and PR transition from functionally distinct in normal breast to predictors of metastatic disease

Cumulative exposure to estrogen (E) and progesterone (P) over the menstrual cycle significantly influences the risk of developing breast cancer. Despite the dogma that PR in the breast merely serves as a marker of an active estrogen receptor (ER), and as an inhibitor of the proliferative actions of E, it is now clear that in the breast P increases proliferation independently of E action. We show here that the progesterone receptor (PR) and ER are expressed in different epithelial populations, and target non-overlapping pathways in the normal human breast. In breast cancer, PR becomes highly correlated with ER, and this convergence is associated with signaling pathways predictive of disease metastasis. These data challenge the established paradigm that ER and PR function co-operatively in normal breast, and have significant implications not only for our understanding of normal breast biology, but also for diagnosis, prognosis and/or treatment options in breast cancer patients.     

Body size and composition and risk of postmenopausal breast cancer.

BACKGROUND: Studies of postmenopausal breast cancer have reported positive associations with body size and composition but it is uncertain whether these are due to non-adipose, adipose mass, or central adiposity, and whether they are limited to subgroups defined by age or tumor characteristics.METHODS: In a prospective cohort study of women ages 27 to 75, body measurements were taken directly; fat mass and fat-free mass being estimated by bioelectrical impedance analysis, and central adiposity by waist circumference. Among 13,598 women followed on average for 9.1 years, 357 invasive breast cancers were ascertained via the population cancer registry. Data were obtained on estrogen receptor and progesterone receptor status, grade, and stage.RESULTS: Estimates of body size such as fat-free mass [hazard ratio per 10 kg increase = 1.45, 95% confidence interval (CI) 1.16-1.82], fat mass (hazard ratio per 10 kg increase = 1.18, 95% CI, 1.06-1.31), and waist circumference (hazard ratio per 10 cm increase = 1.13, 95% CI, 1.03-1.24) were associated with breast cancer risk. There was no association with risk before 15 years postmenopause. About 15 years after menopause, risk increased sharply and remained elevated. There was some evidence that this association might be stronger for estrogen receptor-positive and poorly differentiated tumors but no evidence that it differed by stage.CONCLUSION: Given that elements of body size and composition are positively associated with breast cancer risk, although not until 15 or more years postmenopause, it is possible that women could reduce risk by maintaining ideal body weight after menopause.     

乳腺癌与甲状腺疾病关系研究进展

乳腺癌与甲状腺疾病均好发于女性,严重影响女性的身心健康。乳腺癌患者在发病前后罹患甲状腺疾病的风险较其他恶性肿瘤高,两者之间存在着一些共同的危险因素,且乳腺和甲状腺同属于激素应答性器官,在一些调控通路之间两者也能相互影响。目前认为碘、甲状腺激素受体和雌激素受体是乳腺癌与甲状腺疾病关系密切可能的发病机制。文章通过分析近年来乳腺癌与甲状腺良性疾病、甲状腺癌、甲状腺激素及抗体关系的研究,探讨乳腺癌与甲状腺疾病之间的关系,为疾病的防治提供依据。     

Body weight and postmenopausal breast cancer risk defined by estrogen and progesterone receptor status among Swedish women: A prospective cohort study

Although obesity is one of the established risk factors for postmenopausal breast cancer, it is not clear whether this positive association differs across estrogen receptor (ER) and progesterone receptor (PR) status of breast tumors. We evaluated the association between body weight and ER/PR defined breast cancer risk stratified by postmenopausal hormone (PMH) use and a family history of breast cancer in the population-based Swedish Mammography Screening Cohort comprising 51,823 postmenopausal women. Relative body weight was measured by body mass index (kg/m2) based on self-reported weight and height collected in 1987 and 1997. Relative risks (RRs) were estimated by hazard ratios derived from Cox proportional hazards regression models. During an average of 8.3-year follow-up, 1,188 invasive breast cancer cases with known ER and PR status were diagnosed. When comparing to normal weight group, we observed a positive association between obesity and risk for the development of ER+ PR+ tumors (RR = 1.67, 95% CI = 1.34-2.07) and an inverse association for the development of all PR- tumors (RR = 0.68, 95% CI = 0.47-0.98). Statistically significant heterogeneity was observed in the RRs between ER+ PR+ tumors and all PR- tumors (p(heterogeneity) < 0.0001). The positive association of obesity with the development of ER+ PR+ tumors was confined to never-users of PMHs (RR = 1.90 (CI 95%:1.38-2.61)) and to those without a family history of breast cancer (RR = 1.82 (CI 95%:1.45-2.29)). Our results support the hypothesis that excess endogenous estrogen due to obesity contributes to an increased risk of ER+ PR+ postmenopausal breast cancer.     

乳腺癌相关雄激素受体的研究进展

雌激素、孕激素受体和人表皮生长因子受体2的表达水平与乳腺癌预后关系密切,是治疗乳腺癌的重要靶点。研究发现,雄激素受体（AR）与乳腺癌的发生、发展、复发、转移及预后转归相关,可能成为影响乳腺癌预后的一个指标。目前,AR在乳腺癌领域的研究陆续展开,已成为一个新的热点。本文就AR与乳腺癌关系的研究现状作初步探讨。     

IBIS II: a breast cancer prevention trial in postmenopausal women using the aromatase inhibitor anastrozole

Tamoxifen has been shown to reduce the incidence of estrogen receptor-positive breast cancer by approximately 50% in high-risk women. Similar results are seen for raloxifene, but it has a more favorable side-effect profile. Data on contralateral tumors from women in adjuvant trials treated with aromatase inhibitors suggest that new tumors can be reduced by another 50% with these drugs, suggesting a potential 75% reduction of estrogen receptor-positive tumors when used in a prophylactic manner. Side effects appear to be fewer with the aromatase inhibitors, with no excess of gynecologic (including endometrial cancer) or thromboembolic events, but an increase in fracture risk and joint symptoms does occur. IBIS II is a placebo-controlled prevention trial evaluating 5 years of the aromatase inhibitor anastrozole in high-risk postmenopausal women. The primary end point is breast cancer incidence, but major efforts are also being directed at minimizing any fracture risk.     

An estrogen receptor genetic polymorphism and a history of spontaneous abortion — Correlation in women with estrogen receptor positive breast cancer but not in women with estrogen receptor negative breast cancer or in women without cancer

Summary We previously identified a polymorphism in the human estrogen receptor gene. In a preliminary study on women with estrogen receptor positive (ER⁺) breast tumors, we found that the presence of the rarer of the two alleles, the B' allele, is correlated with a history of spontaneous abortion. Because that study evaluated only women with estrogen receptor positive (ER⁺) breast cancer, it was unknown whether the observed correlation was restricted to the cancer group or was independent of breast cancer. We have now extended our analysis to include not only additional women with ER⁺ breast cancer, but also those with estrogen receptor negative (ER^–) breast cancer and women without cancer. Results of the current study continue to show an association between the B' allele and a history of spontaneous abortion in the ER⁺ breast cancer group. There was no such correlation either in the ER^– breast cancer group or in the group without cancer. Also, we continue to observe, in the ER⁺ breast cancer group, a significantly higher concentration of ER protein in tumors from homozygous wild type women (genotype BB), than in the tumors from women who are heterozygous for the rarer allele (genotype BB'). We conclude that the combination of spontaneous abortion and the BB' ER genotype may be a marker for breast cancer susceptibility.     

IBIS II: a breast cancer prevention trial in postmenopausal women using the aromatase inhibitor anastrozole

Tamoxifen has been shown to reduce the incidence of estrogen receptor-positive breast cancer by approximately 50% in high-risk women. Similar results are seen for raloxifene, but it has a more favorable side-effect profile. Data on contralateral tumors from women in adjuvant trials treated with aromatase inhibitors suggest that new tumors can be reduced by another 50% with these drugs, suggesting a potential 75% reduction of estrogen receptor-positive tumors when used in a prophylactic manner. Side effects appear to be fewer with the aromatase inhibitors, with no excess of gynecologic (including endometrial cancer) or thromboembolic events, but an increase in fracture risk and joint symptoms does occur. IBIS II is a placebo-controlled prevention trial evaluating 5 years of the aromatase inhibitor anastrozole in high-risk postmenopausal women. The primary end point is breast cancer incidence, but major efforts are also being directed at minimizing any fracture risk.     

V i t D / V D R 与乳腺癌患者免疫状态、临床特征及预后的相关性研究

背景与目的：维生素D（vitamin D，VitD）是一种类固醇激素，外周血25羟基VitD［25-hydroxy VitD，25（OH）D］的血清浓度被认为是体内VitD状态的主要生物标志物，通过检测乳腺癌患者外周血清中25（OH）D的水平，探讨VitD与乳腺癌患者各项临床特征的相关性。方法：对比2015年1月—2018年7月上海交通大学附属第六人民医院收治的乳腺癌患者109例、乳腺良性肿瘤患者50例及健康体检者2 000例的外周血血清中25（OH）D的水平差异，并进一步检测乳腺癌患者的T细胞免疫功能、NK细胞水平，同时应用免疫组织化学方法检测乳腺癌患者癌组织中VitD受体（VitD receptor，VDR）的表达。结果：乳腺癌患者外周血中25（OH）D水平显著低于乳腺良性肿瘤患者和健康体检者，差异有统计学意义（P ＜0.05）。乳腺良性肿瘤患者与健康体检者外周血25（OH）D水平无明显差异（P＞0.05）。乳腺癌患者外周血25（OH）D水平与患者T细胞免疫功能（CD4⁺/CD8⁺比值）、临床分期、淋巴结是否受累、是否骨转移、孕激素受体（progesterone receptor，PR）是否阳性均有显著相关性（P＜0.05），而与肿瘤大小、NK细胞水平、雌激素受体（estrogen receptor，ER）是否阳性无显著相关性（P＞0.05）。乳腺癌组织VDR的表达与乳腺癌患者的T细胞免疫功能、临床分期、肿瘤大小、是否骨转移、是否淋巴结转移均无显著相关性（P＞0.05），而与ER、PR是否阳性具有显著相关性（P ＜0.05）。结论：外围血中VitD水平低可能与乳腺癌发病风险高、T细胞免疫功能低下及预后差有关。     

Weight and weight changes in early adulthood and later breast cancer risk

Obesity is a well‐established cause of postmenopausal breast cancer. However, early life adiposity is inversely associated with breast cancer incidence. To understand these conflicting relations, we use validated measures to assess adiposity in childhood and late adolescence, as well as weight change, in relation to total invasive breast cancer incidence and receptor subtypes. We conducted a prospective observational study among 74,177 women from the Nurses’ Health Study from 1980–2012, with updated risk factors every 2 years during which 4,965 incident invasive breast cancers occurred. Overall, weight at age 18 was inversely associated with both premenopausal (HR per 30 kg = 0.52, 95% CI = 0.39–0.71) and postmenopausal (HR per 30 kg = 0.81, 95% CI = 0.72–0.92) breast cancer which was largely explained by adiposity at age 10. Long‐term weight gain from age 18 both during premenopause and postmenopause were positively associated with postmenopausal breast cancer risk. However, premenopausal weight gain was not related to premenopausal breast cancer risk. Furthermore, weight gain since age 18 was positively associated with ER+/PR+ postmenopausal breast cancer (HR per 30 kg = 1.50, 95% CI = 1.36–1.65) but not ER+/PR? (HR per 30 kg = 0.96, 95% CI = 0.78–1.19) or ER?/PR? (HR per 30 kg = 1.16, 95% CI = 0.95–1.42) postmenopausal breast cancer. Overall, 17% of ER+/PR+ postmenopausal breast cancer and 14% of total postmenopausal breast cancer are attributable to weight gain of > 5 kg since age 18.     

三阴乳腺癌的临床病理特征和预后分析

背景与目的:三阴性乳腺癌(triple negative breast cancer,TNBC)是一类高危乳腺癌,其雌激素受体(estrogen receptor,ER)、孕激素受体(progesterone,PR)和入表皮生长因子受体2(human epidermal growth factor receptor-2.Her-2)表达均为阴性,因而不能从针对激素受体的内分泌治疗和Her-2的靶向治疗中获益.本研究旨在分析TNBC患者的临床病理特征、生存情况和预后影响因素.方法:收集免疫组织化学检测ER、PR和Her-2均为阴性的128例乳腺癌患者的临床病理资料,观察其长期生存情况.结果:所有患者中,浸润性导管癌占89.0%.T1、T2患者占78.1%,有淋巴结转移的患者占48.4%,Ⅰ、Ⅱ期患者占60.9%.5年无病生存率、无局部复发生存率、无远处转移生存率和总生存率分别为71.1%、84.3%、75.8%和83.6%.单因素分析结果显示,淋巴结转移、肿块大小、分期和脉管癌栓与TNBC预后有关.多因素分析显示,淋巴结转移(RR=17.449,P=0.000)、原发肿块大小(RR=31.237,P=0.000)是影响TNBC预后的因素.结论:TNBC有明显不同的临床病理特征,发病时常年轻、有淋巴结转移、肿块较大,有乳腺癌家族史,预后差,淋巴结转移和肿块大小是影响TNBC预后的因素.     

Estrogen and estrogen receptors of breast cancer.

Human breast cancer can be divided into a group that contains specific receptor sites for estrogen and a group without such specific estrogen-binding sites. The presence of specific estrogen receptors in some tumors indicating hormonal dependency has been shown to be of predictive value for endocrine treatment. This would greatly improve therapeutic planning for patients with breast cancer. Tumor tissue from 52 patients was investigated for content of both cytosol estrogen and estrogen receptor. In addition, the total tumor estrogen was also determined in 14 of these tumors. The results of this investigation show two distinct groups: one group containing both estrogen receptor and estrogen and a second group with no receptor but with measurable amount of estrogen. Tumors with estrogen receptors have higher tissue levels of estrogen than tumors without specific estrogen receptor. Even in the absence of estrogen recptor, however, most tumor tissue examined contained a measurable amount of estrogen.     

Selective estrogen receptor modulation: the search for an ideal hormonal therapy for breast cancer

Female hormones, especially estrogens, play an important role in the pathogenesis of breast neoplasms and are a principal determinant of their biological behavior. Endocrine manipulation through medical or surgical means can often lead to objective shrinkage of breast tumors. Tamoxifen, a triphenylethylene estrogen receptor modulator, is currently the most widely used hormonal treatment for breast cancer. It has been conclusively demonstrated to reduce the risk of relapse following definitive local therapy (and systemic chemotherapy, when indicated) of invasive or noninvasive breast cancer. Recently, it has also been shown to reduce the incidence of breast cancer in healthy women who are at high risk of developing the disease. In addition, it can prevent osteoporosis and reduce the risk of fractures in postmenopausal women. However, its use is also complicated by an increased incidence of endometrial hyperplasia/carcinoma, venous thromboembolism, cataracts, and in some cases, emergence of tamoxifen-dependent clones of breast cancer. These side effects (except cataracts) are believed to be related to estrogen-agonist effects of tamoxifen. Newer drugs, which are “pure antiestrogens” or inhibitors of estrogen biosynthesis, are devoid of such estrogen-agonist activity and may not have the liability of many of these side effects. However, these agents would also be expected to lack the potentially beneficial effects of tamoxifen on lipids and skeletal system. The ability of tamoxifen to act as an estrogen-agonist or estrogen-antagonist in a tissue-specific fashion has led to the concept of selective estrogen-receptor modulation. Selective estrogen receptor modulators (SERMs), which are devoid of estrogenagonist effects on the uterus or breast cancer cells but retain potentially beneficial effects on bones and lipids, have been described as “ideal” SERMs. A number of such compounds are currently being tested. Raloxifene is already approved for prevention of osteoporosis and has potential efficacy for prevention and treatment of breast cancer. An analogue of raloxifene, LY353381, is currently in Phase II clinical trials for treatment of breast cancer, with promising early results. EM800 and CP336156 are other promising ideal SERMs in clinical trials. These compounds may provide better treatment and chemoprevention alternatives for breast cancer as compared to tamoxifen, aromatase inhibitors, and pure antiestrogens. In addition, they may also prove to be useful for the treatment and prevention of prostate cancer as well as for treating benign gynecological diseases such as fibroids and endometriosis. Future laboratory efforts should focus on further broadening the efficacy profile of SERMs (e.g., prevention of Alzheimer's disease and elevation of high-density lipoproteins to improve the likelihood of cardiovascular benefit) and narrowing their side-effect profile (e.g., risk of thromboembolism and hot flashes).     

Adult weight gain and histopathologic characteristics of breast cancer among postmenopausal women

BACKGROUND: Although the link between postmenopausal breast cancer and adiposity is well established, the association between weight gain and specific histopathologic characteristics of breast carcinoma has not been studied carefully. METHODS: Using 1200 incident invasive breast cancers among 44,161 postmenopausal women who were not taking hormone therapy in the American Cancer Society's Cancer Prevention Study II Nutrition Cohort, the authors computed age-adjusted rates and rate ratios (RR) for breast cancer by histology, stage, grade, and estrogen receptor (ER) and progesterone receptor (PR) status by categories of adult weight gain. RESULTS: Age-adjusted rates of breast cancer were highest for women who reported the most weight gain, regardless of histologic type. For weight gain >60 pounds, compared with weight gain < or =20 pounds the RR for ductal carcinoma was 1.89 (95% confidence interval [95%CI], 1.53-2.34), and the RR for lobular carcinoma was 1.54 (95%CI. 1.01-2.33). Weight gain was associated with increased risk at every tumor stage and grade. The risk for regional or distant stage was elevated significantly in every category of weight gain and was 3 times higher among women who had the greatest weight gain (RR, 3.15; 95%CI, 2.21-4.48). Weight gain was associated with increased risk of ER-positive/PR-positive tumors (P for trend <.0001) but not ER-negative/PR-negative tumors (P for trend = .09). The results essentially remained unchanged when the analysis was restricted to women who had regular screening mammograms. CONCLUSIONS: Excess adiposity is an important contributor to breast cancer risk among postmenopausal women, regardless of histologic type, and especially for tumors of advanced stage and high grade.     

Etiology of hormone receptor-defined breast cancer: a systematic review of the literature.

Breast cancers classified by estrogen receptor (ER) and/or progesterone receptor (PR) expression have different clinical, pathologic, and molecular features. We examined existing evidence from the epidemiologic literature as to whether breast cancers stratified by hormone receptor status are also etiologically distinct diseases. Despite limited statistical power and nonstandardized receptor assays, in aggregate, the critically evaluated studies (n = 31) suggest that the etiology of hormone receptor-defined breast cancers may be heterogeneous. Reproduction-related exposures tended to be associated with increased risk of ER-positive but not ER-negative tumors. Nulliparity and delayed childbearing were more consistently associated with increased cancer risk for ER-positive than ER-negative tumors, and early menarche was more consistently associated with ER-positive/PR-positive than ER-negative/PR-negative tumors. Postmenopausal obesity was also more consistently associated with increased risk of hormone receptor-positive than hormone receptor-negative tumors, possibly reflecting increased estrogen synthesis in adipose stores and greater bioavailability. Published data are insufficient to suggest that exogenous estrogen use (oral contraceptives or hormone replacement therapy) increase risk of hormone-sensitive tumors. Risks associated with breast-feeding, alcohol consumption, cigarette smoking, family history of breast cancer, or premenopausal obesity did not differ by receptor status. Large population-based studies of determinants of hormone receptor-defined breast cancers defined using state-of-the-art quantitative immunostaining methods are needed to clarify the role of ER/PR expression in breast cancer etiology.     

乳腺癌C-erbB-2癌基因与雌激素和孕激素受体的关系及其意义

目的　探讨乳腺癌C -erbB - 2癌基因与雌激素和孕激素受体的关系及其意义。方法　采用免疫组化方法 (二步法 ) ,检测 83例乳腺癌组织中C -erbB - 2、ER、PR的表达。结果　C -erbB - 2、ER、PR在乳腺癌组织中表达阳性率为 5 7 83%、71 0 8%、6 6 2 7%。C -erbB - 2表达 :在ER、PR阴性组高于ER、PR阳性组 (P <0 0 5 ) ;在淋巴结转移组的乳腺癌高于淋巴结未转移组 (P <0 0 5 )。结论　C -erbB - 2与ER、PR联合检测 ,对于乳腺癌患者术后选择个性化化疗具有指导意义 ,也是衡量预后的重要指标。     

Dietary lignan intakes and risk of breast cancer by tumor estrogen receptor status

We examined the association of dietary lignan intake with estrogen receptor negative (ER−) and ER positive (ER+) breast cancer risk in a breast cancer case–control study. Among premenopausal women only, there was a reduced risk of ER− breast cancer for those in the highest compared to the lowest quartile of lignan intake suggesting that the observed negative association of lignans with breast cancer may be limited to ER− tumors.     

Haplotypes of the estrogen receptor beta gene and breast cancer risk

Exposure to exogenous (oral contraceptives, postmenopausal hormone therapy) and endogenous (number of ovulatory cycles, adiposity) steroid hormones is associated with breast cancer risk. Breast cancer risk associated with these exposures could hypothetically be modified by genes in the steroid hormone synthesis, metabolism and signaling pathways. Estrogen receptors are the first step along the path of signaling cell growth and development upon stimulation with estrogens. The National Cancer Institute Breast and Prostate Cancer Cohort Consortium has systematically selected haplotype tagging SNPs in genes along the steroid hormone synthesis, metabolism and binding pathways, including the estrogen receptor beta (ESR2) gene. Four htSNPs tag the 6 major (>5% frequency) haplotypes of the ESR2 gene. These polymorphisms have been genotyped in 5,789 breast cancer cases and 7,761 controls nested within the American Cancer Society Cancer Prevention Study II, European Prospective Investigation into Cancer and Nutrition, Multiethnic Cohort, Nurses' Health Study and Women's Health Study cohorts. None of the SNPs were independently associated with breast cancer risk. One haplotype of the ESR2 gene was associated with breast cancer risk before correction for multiple testing (OR 1.17, 95% CI 1.07-1.28, p = 0.0007). This haplotype remained associated with breast cancer risk after adjustment for multiple testing using a permutation procedure. There was no statistically significant heterogeneity in SNP or haplotype odds ratios across cohorts. These data suggest that inherited variants in ESR2 (while possibly conferring a small increased risk of breast cancer) are not associated with appreciable (OR > 1.2) changes in breast cancer risk among Caucasian women.     

Electromagnetic Fields and Female Breast Cancer

The possibility that long term exposure to relatively weak power frequency electromagnetic fields (EMF) could increase the risk of breast cancer has been investigated during the past decade. The hypothesis is based on the assumption that magnetic field exposures suppress melatonin production and that melatonin is protective against breast cancer. Most epidemiological studies have indicated little or no overall effect of EMF exposure, but some early studies suggested effects among premenopausal women, particularly for estrogen receptor positive breast tumors. The early studies were often limited by small numbers, crude exposure information and lack of information on confounding factors. In more recent occupational studies, again no overall risk increases were reported, but some studies found increased risks in certain subgroups, although with no consistent pattern across studies. A recent very large occupational study with improved exposure assessment and enough statistical power also for subgroup analyses found no indications of increased risks in any subgroups. Most of the recent well-designed residential studies report no increased risks, and similar findings are reported in the majority of studies of bed heating devices. Overall, the weight of the evidence available today does not suggest an increased risk of breast cancer related to EMF exposure.     

Antidepressant use and breast cancer risk

Summary Background Antidepressants are among the most commonly prescribed drugs in the United States. Laboratory studies suggest that because certain antidepressants increase prolactin levels that they may also increase breast cancer risk. However, human studies evaluating use of antidepressants in relation to breast cancer risk have yielded inconsistent results. Methods A population-based case-control study consisting of 975 breast cancer cases 65–79 years of age diagnosed from 1997–1999 and 1007 age and residence-matched controls was conducted in western Washington State. Detailed information on antidepressant use was obtained through structured in-person interviews. Logistic regression was performed to analyze the relationship between antidepressant use and breast cancer risk. Results Overall, there was no association between ever use of antidepressants and breast cancer risk (odds ratio [OR] = 1.2, 95% confidence interval [95% CI]: 0.9–1.6). When evaluated separately, tricyclic antidepressants (TCA), selective serotonin reuptake inhibitors (SSRI), and triazolopyridines were each not associated with breast cancer risk. However, risk varied by hormone receptor status. Compared to never users, ever users of SSRIs had elevated risks of progesterone receptor (PR) negative and estrogen receptor (ER) positive/PR-negative breast cancers (OR = 1.8, 95% CI: 1.1–3.6 and OR = 2.0, 95% CI: 1.1–3.8, respectively), but not of tumors with other hormone receptor profiles. Conclusions Based on these results and those of previous studies, there is limited evidence that any type of antidepressant use is associated with breast cancer risk overall. SSRIs may elevate risks of PR- and ER+/PR- tumors, though further studies are needed to confirm these associations.