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Introduction: The U.S. Preventive Services Task Force recommends breast, cervical, and colorectal cancer screening to reduce mortality from these cancers, but screening use has been below national targets. The purpose of this study is to examine the proportion of screening-eligible adults who are up to date with these screenings and how screening use compares with Healthy People 2020 targets., Methods: Data from the 2019 National Health Interview Survey were used to examine the percentages of adults up to date with breast cancer screening among women aged 50‒74 years without previous breast cancer, cervical cancer screening among women aged 21‒65 years without previous cervical cancer or hysterectomy, and colorectal cancer screening among adults aged 50‒75 years without previous colorectal cancer. Estimates are presented by sociodemographic characteristics and healthcare access factors. Analyses were conducted in 2021., Results: Percentages of adults up to date were 76.2% (95% CI= 75.0, 77.5) for breast cancer screening, 76.4% (95% CI= 75.2, 77.6) for cervical cancer screening, and 68.3% (95% CI= 67.3, 69.3) for colorectal cancer screening. Although some population subgroups met breast and colorectal cancer screening targets (81.1% and 70.5%, respectively), many did not, and cervical cancer screening was below the target for all examined subgroups. Lower education and income, nonmetropolitan county of residence (which included rural counties), no usual source of care or health insurance coverage, and Medicaid coverage were associated with lower screening test use., Conclusions: Estimated use of breast, cervical, and colorectal cancer screening tests based on the 2019 National Health Interview Survey were below national targets. Continued monitoring may allow for examination of screening trends, inform interventions, and track progress in eliminating disparities., (Published by Elsevier Inc.)

Purpose Women undergoing diagnosis and treatment for breast cancer may face challenges in employment. We investigated the impact of demographic, clinical, workplace, and psychosocial characteristics on loss of employment after a breast cancer diagnosis and treatment. We further describe changes in work status and work environment for cancer survivors who sustain employment. Methods We analyzed responses from a survey of breast cancer survivors from the Sister Study and the Two Sister Study cohorts who reported being employed at the time of their breast cancer diagnosis and who reported employment status (lost vs. sustained employment) at the time of survey administration. Multivariate logistic regression was used to identify the effects of lymphedema, neuropathy, problems with memory or attention, social support, health insurance, and sick leave on lost employment, adjusting for demographic characteristics, cancer stage, treatment, and general health. Results Of the 1675 respondents who reported being employed at the time of diagnosis, 83.5% reported being 'currently' employed at the time of the survey. Older age, peripheral neuropathy, lack of sick leave, late stage at diagnosis, a recurrence or a new cancer, problems with memory or attention, and poor general health were significantly associated with lost employment. Conclusions The long-term effects of breast cancer treatment and workplace provisions for leave and accommodation may have a substantial effect on women's ability to sustain employment. The findings from this study highlight challenges reported by cancer survivors that may inform clinical and occupational interventions to support survivors' return to work., (© 2021. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Purpose: The death rate for female breast cancer increases progressively with age, but organizations differ in their mammography screening recommendations for older women. To understand current patterns of screening mammography use and breast cancer diagnoses among older women, we examined recent national data on mammography screening use and breast cancer incidence and stage at diagnosis among women aged ≥ 65 years., Methods: We examined breast cancer incidence using the 2016 United States Cancer Statistics dataset and analyzed screening mammography use among women aged ≥ 65 years using the 2018 National Health Interview Survey., Results: Women aged 70-74 years had the highest breast cancer incidence rate (458.3 cases per 100,000 women), and women aged ≥ 85 years had the lowest rate (295.2 per 100,000 women). The proportion of cancer diagnosed at distant stage or with unknown stage increased with age. Over half of women aged 80-84 years and 26.0% of women aged ≥ 85 years reported a screening mammogram within the last 2 years. Excellent/very good/good self-reported health status (p = .010) and no dependency in activities of daily living/instrumental activities of daily living (p < .001) were associated with recent mammography screening., Conclusion: Breast cancer incidence rates and stage at diagnosis vary by age. Many women aged ≥ 75 years receive screening mammograms. The results of this study point to areas for further investigation to promote optimal mammography screening among older women.

Advances in breast cancer science, early detection, and treatment have resulted in improvements in breast cancer survival but not in breast cancer incidence. After skin cancer, breast cancer is the most common cancer diagnosis in the United States. Each year, nearly a quarter million U.S. women receive a breast cancer diagnosis, and the number continues to rise each year with the growth in the population of older women. Although much remains to be understood about breast cancer origins and prevention, action can be taken on the existing scientific knowledge to address the systemic factors that drive breast cancer risk at the population level. The California Breast Cancer Research Program funded a team at Breast Cancer Prevention Partners (BCPP) to convene leaders in advocacy, policy, and research related to breast cancer prevention from across the state of California. The objective was the development of a strategic plan to direct collective efforts toward specific and measurable objectives to reduce the incidence of breast cancer. The structured, innovative approach used by BCPP to integrate scientific evidence with community perspectives provides a model for other states to consider, to potentially change the future trajectory of breast cancer incidence in the United States., Competing Interests: The authors declare no conflict of interest.

Background: The U.S. Preventive Services Task Force recommends biennial screening mammography for average-risk women aged 50-74 years. County-level information on population measures of mammography use can inform targeted intervention to reduce geographic disparities in mammography use. County-level estimates for mammography use nationwide are rarely presented., Methods: We used data from the 2014 Behavioral Risk Factor Surveillance System (BRFSS; n = 130,289 women), linked it to the American Community Survey poverty data, and fitted multilevel logistic regression models with two outcomes: mammography within the past 2 years (up-to-date), and most recent mammography 5 or more years ago or never (rarely/never). We poststratified the data with U.S. Census population counts to run Monte Carlo simulations. We generated county-level estimates nationally and by urban-rural county classifications. County-level prevalence estimates were aggregated into state and national estimates. We validated internal consistency between our model-based state-specific estimates and urban-rural estimates with BRFSS direct estimates using Spearman correlation coefficients and mean absolute differences., Results: Correlation coefficients were 0.94 or larger. Mean absolute differences for the two outcomes ranged from 0.79 to 1.03. Although 78.45% (95% confidence interval, 77.95%-78.92%) of women nationally were up-to-date with mammography, more than half of the states had counties with >15% of women rarely/never using a mammogram, many in rural areas., Conclusions: We provided estimates for all U.S. counties and identified marked variations in mammography use. Many states and counties were far from the 2020 target (81.1%)., Impact: Our results suggest a need for planning and resource allocation on a local level to increase mammography uptake., (©2018 American Association for Cancer Research.)

Although annual breast magnetic resonance imaging (MRI) is recommended for women at high risk for breast cancer as an adjunct to screening mammography, breast MRI use remains low. We examined factors associated with breast MRI use in a cohort of women with a family history of breast cancer but no personal cancer history. Study participants came from the Sister Study cohort, a nationwide, prospective study of women with at least 1 sister who had been diagnosed with breast cancer but who themselves had not ever had breast cancer (n = 17 894). Participants were surveyed on breast cancer beliefs, cancer worry, breast MRI use, provider communication, and genetic counseling and testing. Logistic regression was used to assess factors associated with having a breast MRI overall and for those at high risk. Breast MRI was reported by 16.1% and was more common among younger women and those with higher incomes. After adjustment for demographics, ever use of breast MRI was associated with actual and perceived risk. Odds ratios (OR) were 12.29 (95% CI, 8.85-17.06), 2.48 (95% CI, 2.27-2.71), and 2.50 (95% CI, 2.09-2.99) for positive BRCA1/2 test, lifetime breast cancer risk ≥ 20%, and being told by a health care provider of higher risk, respectively. Women who believed they had much higher risk than others or had higher level of worry were twice as likely to have had breast MRI; OR = 2.23 (95% CI, 1.82-2.75) and OR = 1.76 (95% CI, 1.52-2.04). Patterns were similar among women at high risk. Breast cancer risk, provider communication, and personal beliefs were determinants of breast MRI use. To support shared decisions about the use of breast MRI, women could benefit from improved understanding of the chances of getting breast cancer and increased quality of provider communications., (© 2018 Wiley Periodicals, Inc.)

Purpose: Younger women diagnosed with breast cancer have poorer prognoses and higher mortality compared to older women. Young black women have higher incidence rates of breast cancer and more aggressive subtypes than women of other races/ethnicities. In this study, we examined recent trends and variations in breast cancer incidence among young women in the United States., Methods: Using 2004-2013 National Program of Cancer Registries and Surveillance, Epidemiology, and End Results Program data, we calculated breast cancer incidence rates and trends and examined variations in stage, grade, and tumor subtype by age and race/ethnicity among young women aged 20-49 years., Results: The majority of breast cancer cases occurred in women aged 40-44 and 45-49 years (77.3%). Among women aged < 45 years, breast cancer incidence was highest among black women. Incidence trends increased from 2004 to 2013 for Asian or Pacific Islander (API) women and white women aged 20-34 years. Black, American Indian or Alaska Native, and Hispanic women had higher proportions of cases diagnosed at later stages than white and API women. Black women had a higher proportion of grade III-IV tumors than other racial/ethnic groups. Across all age groups, incidence rates for triple-negative breast cancer were significantly higher in black women than women of other races/ethnicities, and this disparity increased with age., Conclusions: Breast cancer among young women is a highly heterogeneous disease. Differences in tumor characteristics by age and race/ethnicity suggest opportunities for further research into personal and cultural factors that may influence breast cancer risk among younger women.

Introduction: Women facing complex and uncertain situations such as cancer in their families may seek information from a variety of sources to gain knowledge about cancer risk and reduce uncertainty. We describe and assess the relative importance of information sources about familial breast cancer at the individual, family, and healthcare provider levels influencing women's reporting they had enough information to speak with daughters about breast cancer. This outcome we refer to as being informed about breast cancer., Materials and Methods: Sister Study participants, a cohort of women with a family history of breast cancer, were surveyed on family cancer history, family communication, social support, and interactions with healthcare providers (n = 11,766). Adjusted percentages and 95% confidence intervals for being informed about breast cancer versus not being informed were computed for individual-, family-, and provider-level characteristics in three steps using multivariate logistic regression models., Results: We found 65% of women reported being informed about breast cancer while 35% did not. Having a trusted person with whom to discuss cancer concerns, having a lower versus higher perceived risk of breast cancer, having undergone genetic counseling, and being satisfied with physician discussions about breast cancer in their families were predictors of being informed about breast cancer., Conclusions: Although acquiring objective risk information, such as through genetic counseling, may contribute to a basic level of understanding, communication with providers and within other trusted relationships appears to be an essential component in women's reporting they had all the information they need to talk with their daughters about breast cancer.

Purpose: Recommendations for breast cancer screening using mammography target asymptomatic women aged ≥ 40 years who are not at increased risk for breast cancer. Evidence is not available to demonstrate benefits of screening with mammography at younger ages, and little is known about mammography use among younger women. This study described mammography use among women aged 18-39 years., Methods: We analyzed data from the 2011-2015 National Survey of Family Growth, an in-person survey of a nationally representative sample of the U.S. household population. We estimated the prevalence of ever receiving a mammogram and examined reasons for the first mammograms among women aged 18-39 years without personal cancer history (n = 8324). We classified the first mammogram as a screening examination if it was performed either as part of a routine exam or because of family history of cancer., Results: Among women aged 18-39 years, 14.3% (95% CI 13.2-15.4) reported ever having a mammogram. Prevalence of mammography use was highest among women aged 35-39 years (31.0%, 95% CI 27.8-34.5), and was higher among non-Hispanic black women than in other race/ethnicity groups. Women with a family history of breast cancer reported a higher prevalence of mammography use than women without this family history. For both women with and without a family history of breast cancer, about half of all first mammograms were performed for screening reasons., Conclusions: Among U.S. women aged 18-39 years with no personal cancer history, one in seven reported having received a mammogram. Women with no family history of breast cancer were as likely as those with a family history to initiate breast cancer screening with mammography before age 40. Our findings provide evidence that supports further research to examine factors that prompt young women to receive screening mammograms.

Objective: The aim of this study was to identify demographic and treatment-related factors associated with health-promoting behavior changes after a breast cancer diagnosis. Changes in health behaviors were also evaluated according to weight, exercise, diet and alcohol consumption patterns before breast cancer diagnosis., Materials and Methods: We examined self-reported behavior changes among 1415 women diagnosed with breast cancer in the NIEHS Sister Study cohort. Women reported changes in exercising, eating healthy foods, maintaining a healthy body weight, drinking alcohol, smoking, getting enough sleep, spending time with family and friends, and participating in breast cancer awareness events., Results: On average, women were 3.7 years from their breast cancer diagnosis. Overall, 20-36% reported positive changes in exercise, eating healthy foods, maintaining a healthy weight, or alcohol consumption. However, 17% exercised less. With each 5-year increase in diagnosis age, women were 11-16% less likely to report positive change in each of these behaviors (OR = 0.84-0.89; p < 0.05), except alcohol consumption (OR = 0.97; CI: 0.81, 1.17). Women who underwent chemotherapy were more likely to report eating more healthy foods (OR = 1.47; 95% CI 1.16-1.86), drinking less alcohol (OR = 2.01; 95% CI: 1.01, 4.06), and sleeping enough (OR = 1.41; 95% CI: 1.04, 1.91). The majority of women (50-84%) reported no change in exercise, eating healthy foods, efforts to maintain a healthy weight, alcohol consumption, sleep patterns, or time spent with family or friends., Conclusions: Many women reported no change in cancer survivorship guideline-supported behaviors after diagnosis. Positive changes were more common among younger women or those who underwent chemotherapy., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: This study describes variations in mammography and Pap test use across and within subgroups of Asian women in the USA., Methods: Using data from the National Health Interview Survey (2008, 2010, and 2013), we calculated weighted proportions for selected Asian subgroups (Asian Indian, Chinese, Filipino, Other Asian) of women reporting mammography and Pap test use., Results: The proportion of women aged 50-74 years who reported a mammogram within the past 2 years did not differ significantly across Asian subgroups. The proportion of women aged 21-65 years who received a Pap test within the past 3 years differed significantly across Asian subgroups, with lower proportions among Asian Indian, Chinese, and Other Asian women. Recent immigrants, those without a usual source of care, and women with public or no health insurance had lower proportions of breast and cervical cancer screening test use., Conclusions: Patterns of mammography and Pap test use vary among subgroups of Asian women, by length of residency in the USA, insurance status, usual source of care, and type of cancer screening test. These findings highlight certain Asian subgroups continue to face significant barriers to cancer screening test use.

Purpose: This study examined patterns in mammography and Pap test use across and within subpopulations of Hispanic women., Methods: Based on data from the National Health Interview Survey (2008, 2010, and 2013), we estimated the proportion of Hispanic women reporting testing for breast and cervical cancer for specific subgroups. We examined test use by demographic characteristics using Chi-square tests., Results: Overall, the proportion of women aged 50-74 years who reported a mammogram within the past 2 years did not differ significantly across Hispanic subgroups. Among publically and uninsured women, however, proportions of mammography utilization varied significantly across Hispanic subgroups. The proportion of women aged 21-65 years who received a Pap test within the past 3 years differed significantly across Hispanic subgroups., Conclusions: Among subgroups of Hispanic women, patterns in mammography and Pap test use vary by insurance status, length of US residency, and type of screening. Certain subgroups of Hispanic women may benefit from culturally tailored efforts to promote breast and cervical cancer screening.

Regular breast, cervical, and colorectal cancer (CRC) screening with timely and appropriate follow-up and treatment reduces deaths from these cancers. Healthy People 2020 targets for cancer screening test use have been established, based on the most recent U.S. Preventive Services Task Force (USPSTF) guidelines. National Health Interview Survey (NHIS) data are used to monitor progress toward the targets. CDC used the 2013 NHIS, the most recent data available, to examine breast, cervical, and CRC screening use. Although some demographic subgroups attained targets, screening use overall was below the targets with no improvements from 2010 to 2013 in breast, cervical, or CRC screening use. Cervical cancer screening declined from 2010 to 2013. Increased efforts are needed to achieve targets and reduce screening disparities.

This commentary highlights some of the valuable insights gained from a special collection of papers that utilized data from the National Breast and Cervical Cancer Early Detection Program (NBCCEDP) and appear in this special issue. The data and experiences of the NBCCEDP can inform the identification of new opportunities and directions for meeting the cancer screening needs of underserved women in a complex and changing health care environment.

Mammography screening rates in the United States have remained fairly stable over the past decade, and screening rates remain low for some groups. We examined insights from recent public health research on breast cancer screening to identify promising new approaches to improve screening rates and address persistent health disparities in mammography use. We considered this research in the context of the four strategic directions of the National Prevention Strategy: elimination of health disparities, empowered people, healthy and safe community environments, and clinical and community preventive services. This research points to the value of direct outreach and case management services, interventions to support more patient-centered models of care, and more organized, population-based approaches to identify women who are eligible to be screened, encourage participation, and monitor results.

Background: The goal of breast cancer screening is to reduce breast cancer mortality. Mammography is the standard screening method for detecting breast cancer early. Breast MRI is recommended to be used in conjunction with mammography for screening subsets of women at high risk for breast cancer. We offer the first study to provide national estimates of breast MRI use among women in the United States., Methods: We analyzed data from women who responded to questions about having a breast MRI on the 2010 National Health Interview Survey. We assessed report of having a breast MRI and reasons for it by sociodemographic characteristics and access to health care and computed five-year and lifetime breast cancer risk using the Gail model., Results: Among 11,222 women who responded, almost 5% reported ever having a breast MRI and 2% reported having an MRI within the 2 years preceding the survey. Less than half of the women who reported having a breast MRI were at increased risk. Approximately 60% of women reported having the breast MRI for diagnostic reasons. Women who ever had a breast MRI were more likely to be older, Black, and insured and to report a usual source of health care as compared with women who reported no MRI., Conclusions: Breast MRI use may be underused or overused in certain subgroups of women., Impact: As access to health care improves, the use of breast MRI and the appropriateness of its use for breast cancer detection will be important to monitor.

Background: National incidence rates for lobular and ductal breast cancers have not been available previously. Evidence suggests that the increased risk of breast cancer associated with combined hormone replacement therapy use is higher for invasive lobular cancers (ILC) than for invasive ductal cancers (IDC). This study provides U.S. incidence rates for these histologic types for both in situ and invasive cancers and assesses changes in the incidence of these cancers over time., Methods: Data for this study included incident ductal and lobular breast cancer cases diagnosed from 1999 through 2004 in central cancer registries in 44 states and the District of Columbia from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results program. We estimated incidence per 100,000 women by 10-year age groups, race, and ethnicity. We also assessed the percent change in invasive and in situ cancer incidence over time., Results: We observed distinct differences in the change of incidence over time between in situ and invasive lobular and ductal breast cancers. The age-adjusted rates of ILC and IDC declined an average of 4.6% and 3.3% per year, respectively. Overall, ILC decreased 20.5% from 1999 to 2004. The patterns of ductal and lobular in situ cancer incidence were not consistent over time, and the total change was negligible., Conclusion: The declines in ILC observed in our study are consistent with a decrease in cancer incidence related to a reduced use of combined hormone replacement therapy. However, other factors could also be responsible for these changes.

Objective: Although breast cancer incidence and mortality rates have declined, a significant number of women are affected by this disease each year. Mammography is currently the most effective way to detect breast cancer at an early stage when it is most treatable, but there have been reports of decreasing or stagnant mammography use in the United States. For this study, we investigated the trend in mammography use for each state in comparison with the corresponding breast cancer incidence trend., Materials and Methods: We used data from the Behavioral Risk Factor Surveillance System for 2000, 2002, 2004, and 2006 to assess the percentage of women >or= 40 years old who reported undergoing mammography within the past 2 years and data from the National Program of Cancer Registries and the Surveillance, Epidemiology, and End Results Program to assess breast cancer incidence rates from 2000 through 2004, the latest year for which data were available at the time of the study., Results: The majority of states had a decreasing tendency in mammography use from 2000 to 2006. Only one state had a statistically significant increase in reported mammography use, whereas two states had significant decreases. There was a correlation between breast cancer incidence rates and mammography use by states (r = 0.6), but no correlation between the time trends in breast cancer incidence rates and mammography use was observed., Conclusion: There was little statistically significant change in self-reported mammography use from 2000 to 2006. Continued monitoring of breast cancer screening practices and breast cancer incidence trends is important for targeting at-risk populations with effective interventions to improve breast cancer prevention and early detection.

The presence of mRNA transcripts for cytokines in normal and neoplastic human breast tissue has been investigated. Using reverse transcriptase-linked polymerase chain reaction (RT-PCR), we have specifically screened for the following cytokines: interleukin (IL)-1alpha, IL-1beta, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, tumour necrosis factor (TNF)-alpha, TNF-beta and interferon (IFN)-gamma. No significant differences in expression of IL-1alpha, IL-1beta, IL-4, IL-6, TNF-alpha or TNF-beta were observed between the 2 groups of tissues. However, there was a significant difference in expression of IL-8 transcripts (p = 0.0017) which was higher in the neoplastic population. Transcripts for IL-2, IL-3, IL-5, IL-7 and IFN-gamma were not detected in either group. There was no evidence of associations between cytokine expression and tumour histological grade, patient age or lymph node metastases. Correlating tumour types with specific cytokine transcripts revealed high expression of IL-8, and to a lesser extent, IL-8 and TNF-beta irrespective of tumour origin. Analysis of primary epithelial and stromal cultures derived from both types of tissue showed that increased levels of IL-8, but not IL-6, were secreted by cells obtained from tumours. Thus, breast tissue of both normal and neoplastic origin expresses a wide range of cytokines. Increased or aberrant expression of cytokines, in particular IL-8, may be involved in the development/progression of breast cancer.

Using a differential centrifugation method followed by culture in selective medium, we have successfully isolated and maintained individual epithelial and stromal cells from normal (n = 10) and malignant (n = 6) human breast tissue and characterised their phenotype by immunocytochemistry. Further, we have studied expression of the cytokine genes IL-1beta, IL-6, IL-8 and TNF-beta in each cell fraction by RT-PCR and have compared these results with cytokine gene expression in tissue extracts from which primary cultures were derived. In breast tumours, there was near complete absence of IL-1beta in both whole tissue and cell fractions, and in normals it was present in only 3/10 tissue preparations, with increased expression in stromal (6/10) and epithelial (5/10) cell samples. IL-6 was constitutively expressed in all tumour-derived breast tissue samples but down-regulated in tumour cell cultures, with the opposite result in normal breast. Near identical levels of IL-8 expression were found throughout each preparation, irrespective of tissue origin. TNF-beta was expressed in all normal tissue samples, in 9/10 epithelial preparations but in only 6/10 stromal preparations. In tumours, TNF-beta was associated predominantly with whole tissue or stromal samples, with reduced expression in epithelial preparations. Our data confirm that primary cultures of normal and malignant human breast tissue can be successfully separated into epithelial and mesenchymal cell populations and their phenotype can be maintained in culture for up to 30 days. However, this cellular separation does alter the cytokine profiles; therefore, experimental findings with isolated cells should be treated with a caveat.

The enzyme 17 beta-hydroxysteroid dehydrogenase (17-HSD) is a key regulator of intracellular 17 beta-estradiol (E2), which is associated with breast cancer and is influenced by paracrine factors released by breast-cancer fibroblasts. Since the incidence of breast cancer is much higher in females than in males, we have used an in vitro cell culture system to investigate whether male fibroblasts may inhibit breast-cancer genesis by restricting the intracellular accumulation of E2. Fibroblasts were obtained from normal males and females undergoing reduction mammoplasty, and from females with benign or malignant breast lesions. Fibroblast-conditioned medium (CM) was incubated with the established breast-cancer cell line, MCF-7, and its effects on 17-HSD activity were assessed. CM (25% v/v) from male breast fibroblasts had a significant inhibitory effect on reductive 17-HSD, decreasing E2 production. This was in direct contrast to the effects of CM from female breast fibroblasts, which had a powerful stimulatory effect on reductive 17-HSD. RT-PCR allowing simultaneous detection of a range of cytokines was performed on each type of fibroblast. IL-3 mRNA was consistently detected in fibroblasts from male but not female breast tissue. Addition of rhIL-3 to cultures of MCF-7 caused a reduction in 17-HSD activity and addition of a polyclonal antibody directed against IL-3 to male CM completely reversed the inhibitory effects of CM. Thus, male breast fibroblasts may be responsible for secreting IL-3-like factors which, given the considerably lower incidence rates of breast cancer in men, may have a protective effect against breast cancer.

Previous studies have revealed that human breast fibroblasts secrete the cytokine, interleukin-6 (IL-6) which stimulates the ability of MCF-7 human breast carcinoma cells to convert estrone (E1) to the biologically more active 17 beta-estradiol (E2). This is mediated by an increase in reductive 17 beta-hydroxysteroid dehydrogenase (17-HSD) activity. In the studies described here, we have extended our observations using the anti-estrogen, tamoxifen, to demonstrate that in a steady state, endogenous intracellular concentrations of E2 have no effects on reductive 17-HSD activity (E1-->E2), but are already maximally inhibitory for the oxidative reaction (E2-->E1). Increasing intracellular concentrations of E2, however, stimulated the reductive 17-HSD in a dose-dependent manner. IL-6 stimulated the reductive pathway and was synergistic with E2. IL-6 is most likely acting through an E2-dependent mechanism, since tamoxifen completely reversed the effects of E2 and IL-6 separately and in combination. These observations suggest that tamoxifen may reduce intratissular levels of E2 by directly increasing oxidative 17-HSD activity and by blocking the actions of paracrine factors such as IL-6 which increase reductive 17-HSD activity.

It has been demonstrated that reductive 17 beta-hydroxysteroid dehydrogenase activity (17-HSD) in the human breast cancer cell line MCF-7 can be stimulated by 17 beta-estradiol (E2), progesterone (P) and interleukin-6 (IL-6). We have examined the interactive effects of these factors on growth and reductive 17-HSD activity of MCF-7 cells cultured under defined conditions in phenol red-free medium. E2 stimulated growth of MCF-7 cells in a dose-dependent manner, while IL-6 had a growth inhibitory effect and in combination with E2, it reduced or abolished the stimulatory effects of the steroid. Both E2 and IL-6 stimulated 17-HSD activity by a maximum of 2- to 5-fold, but, in combination, the stimulatory effects ranged from 7- to 10-fold, indicating a strong synergism between the 2 factors. P had growth stimulatory effects on MCF-7, but when combined with IL-6 had no further positive or negative growth effects. Both factors stimulated reductive 17-HSD activity and simultaneous treatment with P and IL-6 indicated a synergy between the 2 factors. These results provide evidence of powerful interactive effects between steroidal and paracrine control of human breast epithelial cells in vitro.