Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007124 (ductal carcinoma in situ)
 3,833 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Surrogate biomarkers for risk assessment and efficacy of potential chemopreventive agents are needed to improve the efficiency and reduce the cost of conducting chemoprevention trials. In addition to criteria of sensitivity, specificity, quantifiability, and reproducibility applicable to most potential biomarkers, there are additional specific constraints in developing biomarkers for specific organ sites. In the case of breast tissue, these difficulties include lack of a consensus on the nature of premalignant lesions and the histologic criteria used to define them; even when such a consensus can be evolved, there are limitations in visualizing such lesions without invasive biopsies. Also, knowledge of specific genetic and biochemical changes in premalignant lesions is limited. In addition, the physiology of breast tissue is cyclic, no proven, relevant markers can be studied in a randomly obtained needle aspirate. The earliest determinate lesion that can be recognized in breast tissue is ductal carcinoma in situ (DCIS). At the University of Texas M.D. Anderson Cancer Center, we have initiated a study to develop biomarkers for tamoxifen and 4-hydroxyphenylretinamide by administering one or both of these drugs to women with DCIS or small invasive lesions in the interval between the initial diagnostic core biopsy and definitive surgery. The treatment is to be administered for 2-4 weeks. Proposed biomarkers to be studied include: (a) markers associated with neoplastic phenotypes, e.g., excessive proliferation, alternations of nuclear morphology and angiogenesis; (b) proteins likely to be required for response to the putative chemopreventive agents, e.g., estrogen receptor, nuclear retinoid receptors; (c) markers indicative of intact downstream response pathways, e.g., progesterone receptors; (d) oncogenes and tumor suppressor genes regulated by the proposed chemopreventive agents, e.g., neu, TGF-beta; and (e) potential novel markers of genetic instability that could be studied in randomly obtained needle aspirates, i.e., random chromosomal gains and losses in high risk mammary epithelium. The experience gained in designing and conducting this trial is expected to facilitate development of future chemoprevention trials of breast, as well as other organ site cancers.
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PMID:A phase II chemoprevention trial design to identify surrogate endpoint biomarkers in breast cancer. 874 74

Scatter factor (SF) is an invasogenic and angiogenic cytokine the cellular receptor of which is encoded by a proto-oncogene (c-met). We measured the immunoreactive SF content (nanograms of SF per milligram of protein) in tissue extracts from 166 breast cancers and correlated the values with various known prognostic parameters. Invasive cancers had nearly four times greater SF content than did ductal carcinoma in situ, and the difference was statistically significant (P < 0.02, two-tailed t-test). However, there were no significant differences in SF content among different histological types of invasive cancer. Invasive cancers that had spread to axillary lymph nodes exhibited higher SF content than did invasive cancers without regional spread (P < 0.02), but the difference in SF content between node-positive and node-negative tumors was not as great as that between invasive and ductal carcinoma in situ tumors. There was a trend toward increased SF content in larger primary tumors as compared with smaller tumors, but statistical comparison revealed borderline significance (0.05 < P < 1.0). There was no significant correlation between SF content and other parameters, including estrogen receptor, progesterone receptor, DNA ploidy, S phase, or Scarff-Bloom-Richardson score. We also measured the content of von Willebrand factor (a marker of blood vessels) and interleukin-1 beta (a pro-inflammatory cytokine) in the same tumor extracts. SF content showed a strong positive correlation with von Willebrand factor content (P < 0.001) but did not appear to be correlated with interleukin-1 beta. These findings suggest that SF is correlated with several other clinicopathological indicators of aggressive tumor behavior, consistent with the hypothesis that SF is a biological factor that may play a role in breast cancer pathogenesis.
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PMID:Scatter factor protein levels in human breast cancers: clinicopathological and biological correlations. 890 59

Some of the nuclear retinoic acid receptors (RARs) alpha, beta, and gamma and retinoid X receptors (RXRs) alpha, beta, and gamma are thought to mediate the effects of retinoids on cell growth, differentiation, and apoptosis and thereby prevent breast carcinogenesis. We analyzed the expression of mRNAs for the three RARs and RXR-alpha in histological sections of specimens from 70 breast cancer patients, which included adjacent normal tissue, ductal carcinoma in situ, and invasive cancer, using in situ hybridization. RARs alpha, beta, and gamma and RXR-alpha were expressed in 98.1, 98.0, 93.0, and 100% of the adjacent normal tissues. Significant decreases in the number of cases expressing RAR-beta were observed among ductal carcinoma in situ (83.1%) and invasive carcinomas (51.6%), especially among the poorly differentiated cases (77.4 and 35.7 %, respectively). No relationship was found between the expression of estrogen receptor and RAR-beta. These results implicate decreases in RAR-beta expression in breast cancer development and suggest that they are independent of estrogen receptor status.
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PMID:Progressive decrease in nuclear retinoic acid receptor beta messenger RNA level during breast carcinogenesis. 937 89

Expression of p53 protein was investigated by immunohistochemical techniques in archival cases of 134 primary breast carcinomas comprising 13 comedo ductal carcinoma in situ (DCIS), 105 invasive ductal carcinomas, 7 contained the comedo DCIS component adjacent to the invasive ductal component, 5 invasive lobular carcinomas, three colloid carcinomas and one medullary carcinoma. Overexpression of p53 gene product was studied to determine the association with clinico-pathological parameters and also its relationship to c-erbB2. Overexpression of p53 protein was observed in 31% (4/13) of comedo DCIS, 37% (39/105) of invasive ductal carcinomas, 57% (4/7) of carcinomas containing both the in situ and invasive lesions and all medullary carcinomas. A significant relationship (p < 0.05) was observed between strong immunoreactivity of p53 protein and absence of estrogen receptor, histological grade and c-erbB2 but not with lymph node metastases or age of patient. These observations suggest that overexpression of p53 protein may play an important role in tumor progression from noninvasive to invasive in some breast carcinomas and may have potential as an indicator for poorer prognosis.
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PMID:Immunohistochemical analysis of p53 expression in primary breast carcinomas. 956 57

In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P < .0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P < .0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P = .00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinoma in situ (DCIS). Later detection of these neoplastic conditions was associated (P < or = .016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P = .0005) and secondarily by the Gail risk at 10 years (P = .0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials.
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PMID:Breast cytology and biomarkers obtained by random fine needle aspiration: use in risk assessment and early chemoprevention trials. 958 54

Microdissection of histologically identifiable components from formalin-fixed, paraffin-embedded tissue sections allows molecular genetic analyses to be correlated directly with pathological findings. In this study, we have characterized loss of heterozygosity (LOH) at chromosome 11p15 at different stages of progression in microdissected tumor components from 115 ductal carcinomas of the breast. Microdissected foci of intraductal, infiltrating, and metastatic tumors were analyzed to determine the stage of progression at which LOH at 11p15 occurs. LOH was detected in 43 (37%) of 115 cases. Foci of intraductal carcinoma could be microdissected from 85 cases, of which 30 (35%) showed LOH at some stage of progression. LOH was detected in the intraductal component in 26 of these 30 cases. Interstitial deletions were characterized by using a panel of 10 highly polymorphic markers. The smallest region of overlap (SRO) for LOH at 11p15 was bounded by the markers D11S4046 and D11S1758. LOH at 11p15.5 showed no correlation with estrogen receptor status, the presence of positive lymph nodes, tumor size, histological grade, or long-term survival. We conclude that 11p15 LOH usually occurs early in breast cancer development but less frequently does not develop until the infiltrating or metastatic stages of tumor progression.
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PMID:Loss of heterozygosity on chromosome 11p15 during histological progression in microdissected ductal carcinoma of the breast. 966 58

Intracystic papillary carcinoma (IPC) of the breast is a rare tumor with predilection for elderly women and distinctive pathological features that must be distinguished from ductal carcinoma in situ (DCIS) of papillary type and from invasive papillary carcinoma. The clinical, radiological, and pathological features of 29 cases of IPC are reported. The cases were divided into three groups (IPC alone, associated with DCIS, or associated with invasive carcinoma) and studied in terms of their size, predominant architectural pattern, nuclear grade, and presence of necrosis. Immunohistochemical studies were performed to evaluate the c-erbB2 oncoprotein, estrogen receptors, and ki-67 antigen expression. The median age of the patients was 75 years. Microscopically, nine tumors (31.0%) were IPC alone, nine (31.0%) had IPC associated with DCIS, and 11 (38.0%) were IPC associated with invasive carcinoma. Most of the IPC cases had low or intermediate nuclear grade, no necrosis, strongly expressed estrogen receptor, and was negative for c-erbB-2. Nuclear grade 3 and necrosis were found only in cases of IPC associated with invasive carcinoma. The median Ki-67 antigen expression was 10.6%. One patient with IPC alone had a recurrence 5 years later. Lymph node metastases were found in one patient who had the tumor with the biggest invasive area. IPC is a low-grade carcinoma with overall good prognosis. However, there is a high frequency of DCIS or invasive carcinoma associated with it, and the prognosis of these cases is related to the type, grade, and size of the associated lesions.
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PMID:Intracystic (encysted) papillary carcinoma of the breast: a clinical, pathological, and immunohistochemical study. 978 48

Cyclin D1 protein plays an important part in regulating the progress of the cell during the G1 phase of the cell cycle. The cyclin D1 gene, CCND1, is amplified in approximately 20% of mammary carcinomas, and the protein is over-expressed in approximately 50% of cases. This has led to intensive study to ascertain whether cyclin D1 is a biological marker in breast cancer; however, the clinical work has produced unexpected results. Work in cell lines and in transgenic mice indicate that CCND1 is a weak oncogene and it was expected that, like c-erbB-2, over-expression of cyclin D1 protein would be associated with a poor prognosis. Early immunohistochemical prognostic studies produced equivocal results but we, and others, have recently shown that strong staining for cyclin D1 is more likely to be seen in well differentiated, estrogen receptor positive carcinomas. Furthermore, we have found that over-expression of cyclin D1 is actually associated with a good outcome, both in terms of prognosis and response to endocrine treatment. Cyclin D1 is frequently over-expressed in ductal carcinoma in situ but not in benign breast disease, including atypical ductal hyperplasia; hence its expression appears to be closely linked with carcinogenesis. In order to help explain the apparent beneficial effects of cyclin D1 over-expression, a number of closely associated cell cycle proteins have also been evaluated, including the cyclin dependent kinase inhibitor p27, which blocks the activating effects of cyclin D1. Initial reports show that high levels of p27 are associated with a good prognosis and we have shown a positive association between p27 and cyclin D1 expression. These clinical results of cyclin D1 are an example of how information obtained from basic cell biology studies needs to be complemented by clinical studies to ascertain the true worth of a prognostic marker.
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PMID:Cyclin D1 in breast cancer. 1006 68

Cyclins are regulatory subunits for cyclin dependent kinases in the coordination of the cell cycle. Cyclins can also serve non-cell cycle functions, such as the transactivation of estrogen receptor by cyclin D. Evidence for the participation of the G1 cyclins D and E in breast cancer is summarized, including transgenic and knockout mice, transfections, and expression patterns in cohort studies. Overexpression of cyclin D has been reported in ductal carcinoma in situ (DCIS), and similar overexpression of cyclin E is suggested. Strategies to reduce cyclin expression are discussed as potential prevention efforts.
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PMID:Cyclins and breast cancer. 1006 69

The 5' flanking region of the C3(1) component of the rat prostate steroid binding protein (PSBP) has been used to successfully target the expression of the SV40 large T-antigen (Tag) to the epithelium of both the mammary and prostate glands resulting in models of mammary and prostate cancers which histologically resemble the human diseases. Atypia of the mammary ductal epithelium develops at about 8 weeks of age, progressing to mammary intraepithelial neoplasia (resembling human ductal carcinoma in situ [DCIS]) at about 12 weeks of age with the development of invasive carcinomas at about 16 weeks of age in 100% of female mice. The carcinomas share features to what has been classified in human breast cancer as infiltrating ductal carcinomas. All FVB/N female mice carrying the transgene develop mammary cancer with about a 15% incidence of lung metastases. Approximately 10% of older male mice develop anaplastic mammary carcinomas. Unlike many other transgenic models in which hormones and pregnancy are used to induce a mammary phenotype, C3(1)/Tag mice develop mammary tumors in the mammary epithelium of virgin animals without hormone supplementation or pregnancy. Although mammary tumor development appears hormone-responsive at early stages, invasive carcinomas are hormone-independent, which corresponds to the loss of estrogen receptor-alpha expression during tumor progression. Molecular and biologic factors related to mammary tumor progression can be studied in this model since lesions evolve over a predictable time course. Genomic alterations have been identified during tumor progression, including an amplification of the distal portion of chromosome 6 containing ki-ras and loss of heterozygosity (LOH) in other chromosomal regions. We have demonstrated that stage specific alterations in the expression of genes which are critical regulators of the cell cycle and apoptosis are functionally important in vivo. C3(1)/Tag mice appear useful for testing particular therapies since growth of the mammary tumors can be reduced using chemopreventive agents, cytokines, and an anti-angiogenesis agent.
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PMID:The C3(1)/SV40 T-antigen transgenic mouse model of mammary cancer: ductal epithelial cell targeting with multistage progression to carcinoma. 1071 85


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