Metals and Breast Cancer Risk: A Prospective Study Using Toenail Biomarkers.

The role of metals in breast cancer is of interest because of their carcinogenic and endocrine-disrupting capabilities. Evidence from epidemiologic studies remains elusive, and prior studies have not investigated metal mixtures. In a case cohort nested within the Sister Study (enrolled in 2003-2009; followed through September 2017), we measured concentrations of 15 metals in toenails collected at enrollment in a race/ethnicity-stratified sample of 1,495 cases and a subcohort of 1,605 women. We estimated hazard ratios and 95% confidence intervals for each metal using Cox regression and robust variance. We used quantile g-computation to estimate the joint association between multiple metals and breast cancer risk. The average duration of follow-up was 7.5 years. There was little evidence supporting an association between individual metals and breast cancer. An exception was molybdenum, which was associated with reduced incidence of overall breast cancer risk (third tertile vs. first tertile: hazard ratio = 0.82, 95% confidence interval: 0.67, 1.00). An inverse association for antimony was observed among non-Hispanic Black women. Predefined groups of metals (all metals, nonessential metals, essential metals, and metalloestrogens) were not strongly associated with breast cancer. This study offers little support for metals, individually or as mixtures, as risk factors for breast cancer. Mechanisms for inverse associations with some metals warrant further study.

A Method to Pre-Screen Rat Mammary Gland Whole-Mounts Prior To RNAscope.

RNAscope is a quantitative in situ gene expression measurement technique that preserves the spatial aspect of intact tissue; thus, allowing for comparison of specific cell populations and morphologies. Reliable and accurate measurement of gene expression in tissue is dependent on preserving RNA integrity and the quantitative nature of RNAscope. The purpose of this study was to determine if the quantitative nature of RNAscope was retained following processing and carmine staining of mammary gland whole-mounts, which are commonly used to identify lesions, such as hyperplasia and ductal carcinoma in situ (DCIS). We were concerned that handling and procedures required to visualize microscopic disease lesions might compromise RNA integrity and the robustness of RNAscope. No effect on the quantitative abilities of RNAscope was detected when mammary gland whole-mounts were pre-screened for lesions of interest prior to RNAscope. This was determined in comparison to tissue that had been formalin-fixed and paraffin embedded (FFPE) immediately after collection. The ability to pre-screen whole-mounts allowed unpalpable diseased lesions to be identified without labor-intensive serial sectioning of tissue samples to find diseased tissue. This method is applicable to evaluate mammary gland whole-mounts during normal mammary gland development, function, and disease progression.

The angiotensin receptor blocker, Losartan, inhibits mammary tumor development and progression to invasive carcinoma.

Drugs that target the Renin-Angiotensin System (RAS) have recently come into focus for their potential utility as cancer treatments. The use of Angiotensin Receptor Blockers (ARBs) and Angiotensin-Converting Enzyme (ACE) Inhibitors (ACEIs) to manage hypertension in cancer patients is correlated with improved survival outcomes for renal, prostate, breast and small cell lung cancer. Previous studies demonstrate that the Angiotensin Receptor Type I (AT1R) is linked to breast cancer pathogenesis, with unbiased analysis of gene-expression studies identifying significant up-regulation of AGTR1, the gene encoding AT1R in ER+ve/HER2-ve tumors correlating with poor prognosis. However, there is no evidence, so far, of the functional contribution of AT1R to breast tumorigenesis. We explored the potential therapeutic benefit of ARB in a carcinogen-induced mouse model of breast cancer and clarified the mechanisms associated with its success.Mammary tumors were induced with 7,12-dimethylbenz[α]antracene (DMBA) and medroxyprogesterone acetate (MPA) in female wild type mice and the effects of the ARB, Losartan treatment assessed in a preventative setting (n = 15 per group). Tumor histopathology was characterised by immunohistochemistry, real-time qPCR to detect gene expression signatures, and tumor cytokine levels measured with quantitative bioplex assays. AT1R was detected with radiolabelled ligand binding assays in fresh frozen tumor samples.We showed that therapeutic inhibition of AT1R, with Losartan, resulted in a significant reduction in tumor burden; and no mammary tumor incidence in 20% of animals. We observed a significant reduction in tumor progression from DCIS to invasive cancer with Losartan treatment. This was associated with reduced tumor cell proliferation and a significant reduction in IL-6, pSTAT3 and TNFα levels. Analysis of tumor immune cell infiltrates, however, demonstrated no significant differences in the recruitment of lymphocytes or tumour-associated macrophages in Losartan or vehicle-treated mammary tumors.Analysis of AT1R expression with radiolabelled ligand binding assays in human breast cancer biopsies showed high AT1R levels in 30% of invasive ductal carcinomas analysed. Furthermore, analysis of the TCGA database identified that high AT1R expression to be associated with luminal breast cancer subtype.Our in vivo data and analysis of human invasive ductal carcinoma samples identify the AT1R is a potential therapeutic target in breast cancer, with the availability of a range of well-tolerated inhibitors currently used in clinics. We describe a novel signalling pathway critical in breast tumorigenesis, that may provide new therapeutic avenues to complement current treatments.

Perinatal Exposure to Bisphenol A or Diethylstilbestrol Increases the Susceptibility to Develop Mammary Gland Lesions After Estrogen Replacement Therapy in Middle-Aged Rats.

The development of the mammary gland is a hormone-regulated event. Several factors can dysregulate its growth and make the gland more susceptible to cellular transformation. Among these factors, perinatal exposure to xenoestrogens and hormone replacement therapy has been associated with increased risk of developing breast cancer. Here, we assessed the effects induced by estrogen replacement therapy (ERT) in ovariectomized (OVX) middle-aged rats and whether perinatal exposure to diethylstilbestrol (DES) or bisphenol A (BPA) modified these effects in the mammary gland. Pregnant rats were orally exposed to vehicle, 5 µg DES/kg/day, or 0.5 or 50 µg BPA/kg/day from gestational day 9 until weaning. Then, 12-month-old offspring were OVX and treated with 17ß-estradiol for 3 months. Morphological changes and the percentage of epithelial cells that proliferated or expressed estrogen receptor alpha (ESR1) and progesterone receptor (PR) were analyzed in mammary gland samples of 15-month-old animals. ERT induced lobuloalveolar hyperplasia and ductal cysts in the mammary gland of middle-aged rats, associated with a higher proliferation index of epithelial cells. Perinatal exposure to DES followed by ERT increased the number of cysts and induced the formation of fibroadenoma and ductal carcinoma in situ, without modifying the expression of ESR1 or PR. Also, after 3 months of ERT, BPA-exposed rats had a higher incidence of ductal hyperplasia and atypical lobular hyperplasia than animals under ERT alone. In conclusion, perinatal exposure to xenoestrogens increases the susceptibility of the mammary gland to develop cysts and hyperplastic lesions when confronted with ERT later in life.

Impact of hormone replacement therapy use on mammographic screening outcomes.

PURPOSE: This study aims to measure the impact of HRT use at the time of screening on rates of screen-detected invasive breast cancer (IBC) and ductal carcinoma in situ (DCIS), interval cancers and investigative procedures, within a well-established population-based mammography screening program. METHODS: Using South Australian BreastScreen data from 1998 to 2009 pertaining to 819,722 screening episodes, Poisson regression models were undertaken to estimate the incidence risk ratios (IRR) for various screening outcomes at both the first and subsequent screening rounds, among women who had been using HRT in the 6 months prior to screening compared with those who had not. RESULTS: Current HRT use was associated with increased risk of recall for assessment, biopsy procedures, and breast cancer diagnosis among BreastScreen participants. Risk of screen-detected breast cancer was increased at subsequent screening rounds (IRR = 1.30, 95% confidence interval 1.18-1.34), but not at women's first screening round (1.05, 0.88-1.25). This increased risk applied to IBC (1.35, 1.27-1.45), but not to DCIS (1.04, 0.89-1.23). Interval cancer risk was elevated among HRT users following both the first screen (1.77, 1.33-2.37) and subsequent screening episodes (1.92, 1.72-2.15). CONCLUSIONS: Increased risks of recall, biopsy rates, screen-detected, and interval cancers among HRT users have important implications for population-based breast cancer screening programs. Our findings support the concept that HRT use may increase the growth of preexisting cancers. Lack of effect on DCIS could imply different etiology or time frames for DCIS and IBC development or increased transition from preinvasive to invasive disease due to HRT use.

[Prenatal diethylstilbestrol exposure and breast cancer]. / Exposition anténatale au diéthylstilbestrol et cancer du sein.

Diethylstilbestrol (DES) is a synthetic estrogen prescribed to prevent miscarriages until 1977. Its role in the development of vaginal adenocarcinoma and cervical dysplasia is known and screening codified. Recent cohort studies show that exposure to DES in utero increases breast cancer risk especially after 40 years. This article reports the observation of a breast cancer of exceptional gravity in a patient exposed to DES in utero. It details the risk of breast cancer for "DES daughters" and support possible screening modalities.

Immediate extended latissimus dorsi flap reconstruction after skin-sparing mastectomy for breast cancer associated with paraffinoma: report of a case.

Paraffin oil injection into the breast, which had been used for breast augmentation in the past, can cause various complications. Complete removal of paraffinoma lesions with immediate breast reconstruction using autogenous tissue is a very satisfactory treatment option. However, diffuse random distribution of paraffin oil through the subdermal layer makes it impossible to remove all of the lesions with overlying skin without resulting in a shortage of available skin and poor cosmesis. We herein report the case of a patient with breast cancer associated with paraffinoma, treated with skinsparing mastectomy and axillary node dissection with immediate extended latissimus dorsi flap reconstruction, resulting in good cosmetic outcome, and showing no complications during the wound-healing process.

Characterization of a preclinical model of simultaneous breast and ovarian cancer progression.

Women at increased risk for breast cancer are often also at increased risk for ovarian cancer, reflecting common risk factors and intertwined etiologies for both diseases. Unlike breast cancer prevention, primary ovarian cancer prevention has been impractical due to the low incidence, lack of risk and response biomarkers and difficulties in sampling ovarian tissue. Challenges in the development of ovarian cancer prevention drugs, however, may be circumvented through the development of breast cancer prevention strategies that simultaneously decrease ovarian cancer. In the present study, three commonly used mammary cancer carcinogen models [7,12-dimethylbenz[alpha]anthracene (DMBA), N-methyl-N-nitrosourea (MNU) and estradiol (E2)] were combined with local ovarian DMBA administration to induce progression to mammary and ovarian cancer concurrently in the rat. Animals were treated for 3 or 6 months, and tissue histology as well as proliferation, hormonal and inflammation biomarkers were assessed. Mammary and ovarian morphologies (measured as descriptive histology and dysplasia scores) were normal in vehicle controls. Mammary hyperplasia was observed in DMBA/DMBA (mammary carcinogen/ovarian carcinogen) and MNU/DMBA-treated rats; however, ovarian preneoplastic changes were seldom observed after these treatments. All E2/DMBA-treated rats had mammary hyperplasia, atypia, ductal carcinoma in situ and/or invasive adenocarcinoma, while 50% also developed preneoplastic changes in the ovary (ovarian epithelial and stromal hyperplasia and inclusion cyst formation). In both the mammary gland and ovary, decreased estrogen receptor alpha expression was detected, and in the mammary gland elevated Ki-67 and cyclooxygenase-2 expressions were observed. This combined breast and ovarian cancer rat model (systemic E2 treatment and local ovarian DMBA) may be useful for future dual target breast and ovarian cancer prevention studies.

Comparative analysis of minimally invasive microductectomy versus major duct excision in patients with pathologic nipple discharge.

BACKGROUND: Minimally invasive techniques are being used increasingly in patients with benign and malignant breast diseases. The purpose of this study was to compare the diagnostic yield of 2 groups of patients who underwent either minimally invasive microductectomy or major duct excision for pathologic nipple discharge. METHODS: Two hundred thirty-five patients who underwent nipple exploration and duct excision and were part of an institutional review board-approved database were included in this retrospective analysis. Preoperative imaging, ductal washing cytology, surgical specimen size, and final histopathology were compared among 95 patients who underwent microductectomy by using intraoperative ductoscopy and 140 patients undergoing standard major duct excision. RESULTS: Mean age of patients undergoing microductectomy was 53 versus 55 years in patients undergoing major duct excision. Preoperative mammogram was negative or benign in 92% and suspicious in 8% of patients in both the microductectomy group and the major duct excision group. A ductal abnormality was identified by preoperative ductography in 43 of 56 (77%) patients in the microductectomy group versus 74 of 92 (80%) patients in the major duct excision group. Ductal cytology was benign in 81% and 80% of patients tested, respectively. Mean specimen size was significantly smaller in patients who underwent microductectomy (9.2 cm3) as compared with major duct excision (12.6 cm3). Although the percentage of patients with atypical ductal hyperplasia or lobular carcinoma in situ was similar among the 2 groups (9% vs 10%), only 3 of 95 (3%) patients within the microductectomy group were found to have carcinoma within the resection specimen as compared with 12 of 140 (9%) within the major duct excision group (P = .03). Mean specimen size of the patients diagnosed with carcinoma was 8.6 cm(3) in the microductectomy group as compared with 15.5 cm3 in the major duct excision group (P = .014). CONCLUSIONS: These data confirm that patients who present with single duct pathologic nipple discharge usually have benign pathology as the etiology. However, in a small percentage of patients an occult carcinoma might be present. Major duct excision appears to detect a higher percentage of occult carcinoma when compared with minimally invasive microductectomy, which might be related to the larger sample size of the resection specimen.

Development of early malignant bilateral breast disease in relation to antidepressant treatment.

The aim of this study is to present two rare cases of young female patients who were under antidepressant medication and developed bilateral breast disease; histology confirmed the noninvasive, malignant nature. The role of that type of agents in the breast pathology is briefly discussed, based on the data of the current literature.

Synergistic effects of androgen and estrogen on the mouse uterus and mammary gland.

Many studies have suggested that elevated estrogens and androgens may be etiologically related to the development of breast cancer, endometrial cancer and uterine leiomyomas. We and other investigators have previously shown that estrogen and androgen are synergistic in the induction of mammary carcinogenesis in the Noble rat. However, the mechanisms behind the synergy is unknown, and it is unclear whether such synergy is unique for the Noble rat and for the mammary gland. In this study we treated female FVB mice with 17beta-estradiol (E2) and 5alpha-dihydrotestosterone-bezonate (DHT-B), alone and in combination, using silastic tubing for 2-7 months. The results showed that DHT-B alone induced proliferation of uterine endometrial epithelium and myometrial smooth muscle cells, whereas E2 alone induced much more pronounced growth of endometrial epithelium without affecting smooth muscle cells. Combined treatment with E2+DHT-B caused an even more severe hyperplasia of endometrial epithelium and myometrial muscle cells, compared with the treatment with each hormone alone. Uterine leiomyomas were observed in 2 of 6 mice at 7 months of combined treatment but not in any of 6 or 7 mice receiving each single hormone. DHT-B alone induced growth and secretion of mammary ductal cells, as well as growth of mammary stroma. E2 alone stimulated much more pronounced growth of both ductal cells and alveolar cells and secretion of alveolar cells, but had no effect on mammary stroma. Treatment with both E2 and DHT-B caused more severe hyperplasia of mammary ducts and alveoli, compared to the treatment with each hormone alone. Intraductal hyperplasia occurred early and frequently in the E2+DHT-B- treated mice, but no mammary tumors were observed. These results suggest that E2 and DHT-B have synergistic effects on the growth of uterine endometrial epithelium and myometrial muscle cells, as well as mammary epithelial ducts and alveoli.

Oral contraceptives and the risk of ductal breast carcinoma in situ.

UNLABELLED: Recent evidence suggests that oral contraceptive use is associated with little to no increased risk of invasive breast carcinoma. No study has examined the relationship between oral contraceptive use and the risk of non-invasive breast carcinoma, that is, breast carcinoma in situ. OBJECTIVE: To define the role of oral contraceptive use in the development of breast carcinoma in situ. METHODS: The data are 875 ductal carcinoma in situ (DCIS) cases diagnosed among residents of the state of Connecticut from September 15, 1994 to March 14, 1998 and between the age of 20 and 79 years as well as 999 control subjects. Controls are female Connecticut residents collected via random-digit-dial and frequency matched to the cases by 5-year age intervals. Telephone interviews were used to collect information on risk factors and cancer screening history. Logistic regression was used to provide maximum likelihood estimates of the odds ratios (OR) with 95% confidence intervals (95% CI). RESULTS: The risk of being diagnosed with DCIS for women who had ever used oral contraceptives was not increased relative to women who had never used them (OR: 1.0, 95% CI: 0.8, 1.2). The risk did not significantly increase with duration of oral contraceptive use, nor with duration of high estrogen use, time since last use, progestin or estrogen type, or age at first use. Furthermore, the association between oral contraceptive use and DCIS risk did not vary by the presence of a family history of breast cancer or by menopausal status. CONCLUSIONS: In these data, no evidence was found for an increased risk of ductal carcinoma in situ associated with the use of oral contraceptives.

Conjugated linoleic acid isomers and mammary cancer prevention.

There is increasing evidence that individual isomers of conjugated linoleic acid (CLA) may have unique biological or biochemical effects. A primary objective of this study was to determine whether there might be differences in the anticancer activity of 9,11-CLA and 10,12-CLA. This was achieved by evaluating the reduction in premalignant lesions and carcinomas in the mammary gland of rats that had been treated with a single dose of methylnitrosourea and given 0.5% of either highly purified CLA isomer in the diet. Our results showed that the anticancer efficacies of the two isomers were very similar. At 6 wk after carcinogen administration, the total number of premalignant lesions was reduced by 33-36%. At 24 wk, the total number of mammary carcinomas was reduced by 35-40%. The concentration of each CLA isomer and its respective metabolites was analyzed in the mammary fat pad. Tissue level of 10,12-CLA was much lower than that of 9,11-CLA. The pool of metabolites from each isomer was very similar between the two groups and represented only a small fraction of total conjugated diene fatty acids. Feeding of 9,11-CLA resulted in minimal changes in other unsaturated fatty acids. In contrast, feeding of 10,12-CLA produced a wider spectrum of perturbations. Small but significant increases in 16:1 and 16:2 were detected; these were accompanied by decreases in 20:2, 20:3, 20:4, 22:4, and 22:6. The above observation suggests that 10,12-CLA might be more potent than 9,11-CLA in interfering with elongation and desaturation of linoleic and linolenic acids. In summary, our study showed that, at the 0.5% dose level, the anticancer activity of 9,11-CLA and 10,12-CLA was very similar, even though accumulation of 10,12-CLA in the mammary tissue was considerably less than that of 9,11-CLA. These confounding changes of the other unsaturated fatty acids in contributing to the effect of 10,12-CLA need to be clarified.

Measuring microvascular density in tumors by digital dissection.

OBJECTIVE: To develop and validate a digital dissection techniquefor measuring the cross-sectional area of blood vessels in histologic sections of tumors routinely stained with hematoxylin and eosin. STUDY DESIGN: The procedure was first validated in four experimental tumors in rats by comparing the results of the digital dissection technique to functional estimates of the blood volume in the tumors as measured by dynamic, contrast-enhanced magnetic resonance imaging. The method was then tested on a variety of experimental and human tumors. RESULTS: The digital dissection technique yielded results that exactly matched the functional measurements of blood volume infour experimental tumors. Digital dissection of 40 additional tumors in rats showed that 21 infiltrating ductal carcinomas had significantly greater microvascular density (MVD) than 19 benign fibroadenomas (12% vs. 7.9%, P=.028 by two-tailed t test). In 10 human breast carcinomas the MVD was consistently greater than the measurement of blood vessel density as identified by immunohistochemical staining for factor VIII. The between-run coefficients of variation for the MVD assay were 12% (n = 5) for a human breast cancer and 18% (n = 5)for an experimental rat tumor. CONCLUSION: The digital dissection technique is a reproducible, objective and accurate method of measuring MVD in sections of tumors that are routinely stained with hematoxylin and eosin.

Atlas and histologic classification of tumors of the rat mammary gland.

Studies performed in experimental animal models have demonstrated that mammary cancer is a complex multistep process that can be induced either by chemicals, radiation, viruses, or genetic factors. Rodent models have been useful for dissecting the initiation, promotion, and progression steps of mammary carcinogenesis. Chemically induced mammary tumors, such as those induced by 7,12-dimethylbenz(a)anthracene and N-methyl-N-nitrosourea, are, in general, hormone-dependent adenocarcinomas whose incidence, number of tumors per animal, tumor latency, and tumor type are influenced by the age, reproductive history, and endocrinologic milieu of the host at the time of carcinogen exposure as well as by diet and the dose of carcinogen administered. There is a need to classify tumors according to their histopathological type because those characteristics have implications in the interpretation of experimental data. In the classification presented here we attempt to provide a working framework for diagnosis of the type of lesions found in the mammary glands of rats treated with chemical carcinogens or radiation and to clarify criteria for establishing the basic biological characteristics of tumors.

Classification of premalignant and malignant lesions developing in the rat mammary gland after injection of sexually immature rats with 1-methyl-1-nitrosourea.

Premalignant and malignant stages of mammary carcinogenesis can be rapidly induced by injecting female rats i.p. with 1-methyl-1-nitrosourea (MNU)3 at 21 days of age. In this paper, the characteristics of this model are briefly reviewed and the histology of the lesions induced is presented and compared to those that occur in humans. Malignant mammary lesions induced in rats injected with MNU at 21 days of age are compared with the lesions that develop when MNU is administered to 50-day-old female rats.

Benign and malignant mammary tumors induced by DMBA in female Wistar rats.

This study pretends to characterize 7, 12-dimetylbenz[a]anthracene-induced benign and malignant tumors. One hundred and twenty female Wistar rats were randomly allocated to two groups: Control Group and Induction Group; IG animals were given a single dose of DMBA and killed 24 weeks after. Other tumors besides breast tumors were diagnosed, mainly tumors of the salivary glands and ovarian benign epithelial tumors. Incidence of breast disorders was about 60%. Macroscopic mammary tumors varied in dimension from 2 mm to 55 mm. Malignant breast tumors (n = 56) were essentially invasive ductal carcinomas (91.1%), G1 (92.2%), presenting histologic characteristics of good prognosis. Predominant benign breast disorders consisted of glandular (68.6%) and atypical (20%) hyperplasias reproducing histologic types of human breast diseases. Different individual susceptibility to DMBA apparently occurs; while some rats never developed neoplasias, others exhibited several tumors.

Effect of energy restriction on the expression of cyclin D1 and p27 during premalignant and malignant stages of chemically induced mammary carcinogenesis.

The restriction of energy intake has a profound inhibitory effect on carcinogenesis, yet the mechanism or mechanisms that account for this effect are unknown. In this experiment, the hypothesis tested was that energy restriction upregulates the expression of p27/kip1, a gene product associated with cell-cycle growth arrest, while downregulating cyclin D1, a protein that combines with cyclin-dependent kinases to promote phosphorylation of retinoblastoma protein and the progression of cells through the cell cycle. We studied levels of these proteins in uninvolved mammary epithelial cells and in mammary intraductal proliferations, ductal carcinomas in situ, and adenocarcinomas induced in response to administration of 1-methyl-1-nitrosourea in animals fed either ad libitum or 90%, 80%, or 60% of ad libitum intake. Protein levels were evaluated immunohistochemically by using computer-assisted image analysis to quantify differences in protein expression among treatment groups. The expression of p27 increased and the expression of cyclin D1 decreased dose-dependently in response to energy restriction. The effect was greater on p27 than on cyclin D1. The hypothesis proposed is that energy restriction inhibits carcinogenesis by arresting cell-cycle progression by regulating p27/kip1.

Injected liquid silicone, chronic mastitis, and undetected breast cancer.

Although the use of injected liquid silicone for breast augmentation has all but ceased since its widespread use in the 1960s, patients with injected silicone are still seen with a multitude of symptoms. Silicone mastitis is a well-documented phenomenon; however, there has been a paucity of information regarding cancer detection in this group of patients. We report 2 patients who presented with chronic mastitis but on further workup were found to have breast cancer. In both patients, early cancer detection was adversely affected by the presence of free liquid silicone. In view of this and other similar case reports, we advise that simple mastectomy be recommended to those patients with breasts inspissated with liquid silicone who not only have suspicious masses but present with recurrent mastitis or a family history of breast cancer.

Derivation of ductlike cell lines from a transplantable acinar cell carcinoma of the rat pancreas.

Two cell lines were derived from a transplantable acinar cell carcinoma that had been established from a primary carcinoma of the pancreas in an azaserine-treated Lewis rat. The cultured tumor cells initially produced amylase, but production of exocrine enzymes ceased after 1-2 weeks in culture. The cultured cells were tumorigenic in Lewis rats, and one line produced solid tumors composed of ductlike structures surrounded by dense fibrous tissue. The second cell line produced partially solid and partially cystic tumors with a mixed phenotype of squamous, mucinous, and glandular areas when it grew in vivo following regrafting. Both cell lines lost structural and immunohistochemical acinar cell markers while acquiring duct cell markers during culture and regrafting. These studies provide strong support for the hypothesis that ductlike carcinomas can arise from neoplastic pancreatic acinar cells in rats.