[Show abstract][Hide abstract] ABSTRACT: In the adult human breast, hyperplastic enlarged lobular unit (HELU) and atypical ductal hyperplasia (ADH) are two common abnormalities that frequently coexist with ductal carcinoma in situ (DCIS). For this reason, they have been proposed as the early steps in a biological continuum toward breast cancer.
We investigated in silico the expression of 369 genes experimentally recognized as involved in establishing and maintaining epithelial cell identity and mammary gland remodeling, in HELUs or ADHs with respect to the corresponding patient-matched normal tissue.
Despite the common luminal origin, HELUs and ADHs proved to be characterized by distinct gene profiles that overlap for 5 genes only. While HELUs were associated with the overexpression of progesterone receptor (PGR), ADHs were characterized by the overexpression of estrogen receptor 1 (ESR1) coupled with the overexpression of some proliferation-associated genes.
This unexpected finding contradicts the notion that in differentiated luminal cells the expression of estrogen receptor (ER) is dissociated from cell proliferation and suggests that the establishing of an ER-dependent signaling is able to sustain cell proliferation in an autocrine manner as an early event in tumor initiation. Although clinical evidence indicates that only a fraction of HELUs and ADHs evolve to invasive cancer, present findings warn that exposure to synthetic progestins, frequently administered as hormone-replacement therapy, and estrogens, when abnormally produced by adipose cells and persistently present in the stroma surrounding the mammary gland, may cause these hyperplastic lesions.
Ai zheng = Aizheng = Chinese journal of cancer 03/2015; 34(1):3. DOI:10.1186/s40880-015-0004-z · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The establishment and maintenance of mammary epithelial cell identity depends on the activity of a group of proteins, collectively called maintenance proteins, that act as epigenetic regulators of gene transcription through DNA methylation, histone modification, and chromatin remodeling. Increasing evidence indicates that dysregulation of these crucial proteins may disrupt epithelial cell integrity and trigger breast tumor initiation. Therefore, we explored in silico the expression pattern of a panel of 369 genes known to be involved in the establishment and maintenance of epithelial cell identity and mammary gland remodeling in cell subpopulations isolated from normal human mammary tissue and selectively enriched in their content of bipotent progenitors, committed luminal progenitors, and differentiated myoepithelial or differentiated luminal cells. The results indicated that, compared to bipotent cells, differentiated myoepithelial and luminal subpopulations were both characterized by the differential expression of four genes involved in cell identity maintenance: CBX6 and PCGF2, encoding proteins belonging to the Polycomb group, and SMARCD3 and SMARCE1, encoding proteins belonging to the Trithorax group. In addition to these common genes, the myoepithelial phenotype was associated with the differential expression of HDAC1, which encodes histone deacetylase 1, whereas the luminal phenotype was associated with the differential expression of SMARCA4 and HAT1, which encode a Trithorax protein and histone acetylase 1, respectively. The luminal compartment was further characterized by the overexpression of ALDH1A3 and GATA3, and the down-regulation of NOTCH4 and CCNB1, with the latter suggesting a block in cell cycle progression at the G2 phase. In contrast, myoepithelial differentiation was associated with the overexpression of MYC and the down-regulation of CCNE1, with the latter suggesting a block in cell cycle progression at the G1 phase.
Ai zheng = Aizheng = Chinese journal of cancer 09/2014; 33(10). DOI:10.5732/cjc.014.10066 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Mammary epithelial cell identity depends on a set of genes epigenetically-regulated by maintenance proteins, the best-characterized of which belong to the Trithorax and Polycomb groups. Perturbations in expression of these proteins may disrupt cell identity and trigger tumor initiation.
The pattern of expression of a panel of genes involved in control of cell identity and mammary gland remodeling was investigated in two precancerous lesions, atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS) and compared to the corresponding histologically normal tissue.
ADH and DCIS showed a close association in overexpression of Polycomb complex components, silencing of Homeobox A (HOXA) cluster gene, and overexpression of the genes involved in estrogen signaling, specifically, forkhead box A1 (FOXA1) and GATA binding protein 3 (GATA3) pioneer factors, and estrogen receptor-1 (ESR1).
Our findings support the hypothesis that disruption of epigenetic control is associated with loss of cell identity and acquisition of a constitutive estrogen-dependent terminally-differentiated luminal phenotype.
Anticancer research 03/2014; 34(3):1307-19. · 1.83 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: During normal postnatal mammary gland development and adult remodeling related to the menstrual cycle, pregnancy, and lactation, ovarian hormones and peptide growth factors contribute to the delineation of a definite epithelial cell identity. This identity is maintained during cell replication in a heritable but DNA-independent manner. The preservation of cell identity is fundamental, especially when cells must undergo changes in response to intrinsic and extrinsic signals. The maintenance proteins, which are required for cell identity preservation, act epigenetically by regulating gene expression through DNA methylation, histone modification, and chromatin remodeling. Among the maintenance proteins, the Trithorax (TrxG) and Polycomb (PcG) group proteins are the best characterized. In this review, we summarize the structures and activities of the TrxG and PcG complexes and describe their pivotal roles in nuclear estrogen receptor activity. In addition, we provide evidence that perturbations in these epigenetic regulators are involved in disrupting epithelial cell identity, mammary gland remodeling, and breast cancer initiation.
Ai zheng = Aizheng = Chinese journal of cancer 07/2013; 33(2). DOI:10.5732/cjc.013.10040 · 2.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Loss of epithelial cell identity and acquisition of mesenchymal features are early events in the neoplastic transformation of mammary cells. We investigated the pattern of expression of a selected panel of genes associated with cell polarity and apical junction complex or involved in TGF-β-mediated epithelial-mesenchymal transition and cell-fate decision in a series of DCIS and corresponding patient-matched normal tissue. Additionally, we compared DCIS gene profile with that of atypical ductal hyperplasia (ADH) from the same patient. Statistical analysis identified a "core" of genes differentially expressed in both precursors with respect to the corresponding normal tissue mainly associated with a terminally differentiated luminal estrogen-dependent phenotype, in agreement with the model according to which ER-positive invasive breast cancer derives from ER-positive progenitor cells, and with an autocrine production of estrogens through androgens conversion. Although preliminary, present findings provide transcriptomic confirmation that, at least for the panel of genes considered in present study, ADH and DCIS are part of a tumorigenic multistep process and strongly arise the necessity for the regulation, maybe using aromatase inhibitors, of the intratumoral and/or circulating concentration of biologically active androgens in DCIS patients to timely hamper abnormal estrogens production and block estrogen-induced cell proliferation.
International Journal of Surgical Oncology 04/2012; 2012:984346. DOI:10.1155/2012/984346
[Show abstract][Hide abstract] ABSTRACT: Objectives: Cell polarity and epithelial morphology are peculiar features of cells forming the terminal ductal lobular unit, and they are early lost during neoplastic transformation because of an epithelial-mesenchymal transition (EMT). To understand these early events we analyzed a set of 125 genes related to cell polarity, EMT and cell-fate decision in 26 breast cancer specimens and corresponding patient-matched normal tissue. Methods: The difference of gene expres-sion was explored by t-paired test. In addition, to evidence latent variables accounting for genes correlations, a Factor Analysis was applied as exploratory technique. Results: Among the 90 differentially expressed genes, those coding for cell-polarity complexes, apical-junctional components and luminal cytokeratins were overexpressed in tumor samples (suggesting a terminally differentiated phenotype) whereas those coding for stemness-associated features or related with EMT were expressed in normal tissues but not in tumor samples, suggesting the persistence of stem/progenitor cells. Factor analysis confirmed these findings and indicated that the difference between tumors and normal tissues can be synthesized in three main features representative of specific molecular/morphological alterations. Conclusions: The a priori definition of a selected panel of genes and the application of an exploratory statistical approach, greatly contrib-ute to reduce the intrinsic biological complexity of tumor specimens and to describe the difference between tumor specimens and corresponding histologically normal tissues.
Advances in Breast Cancer Research 01/2012; 01(02). DOI:10.4236/abcr.2012.12003
[Show abstract][Hide abstract] ABSTRACT: Loss of cell-cell adhesion and cell polarity is commonly observed in tumors of epithelial origin and correlates with their invasion into adjacent tissues and formation of metastases. Growing evidence indicates that loss of cell polarity and cell-cell adhesion may also be important in early stage of cancer. In first part of this review, we delineate the current understanding of the mechanisms that establish and maintain the polarity of epithelial tissues and discuss the involvement of cell polarity and apical junctional complex components in tumor pathogenesis. In the second part we address the clinical significance of cell polarity and junctional complex components in cancer diagnosis and prognosis. Finally, we explore their potential use as therapeutic targets in the treatment of cancer.
[Show abstract][Hide abstract] ABSTRACT: Breast cancer remains a leading cause of morbidity and mortality in women mainly because of the propensity of primary breast tumors to metastasize. Growing experimental evidence suggests that cancer stem cells (CSCs) may contribute to tumor progression and metastasis spread. However, despite the tremendous clinical potential of such cells and their possible therapeutic management, the real nature of CSCs remains to be elucidated. Starting from what is currently known about normal mammary stem/progenitor cells, to better define the cell that originates a tumor or is responsible for metastatic spread, this review will discuss experimental evidence of breast cancer stem cells and speculate about the clinical importance and implications of their evaluation.
Journal of Oncology 02/2008; 2008:492643. DOI:10.1155/2008/492643
[Show abstract][Hide abstract] ABSTRACT: Hormone therapy with tamoxifen has long been the established adjuvant treatment for node-positive, estrogen-receptor-positive breast cancer in postmenopausal women. Since 30-40% of these patients fail to respond, reliableoutcome prediction is necessary for successful treatment allocation. Using pathobiological variables (available in mostclinical records: tumor size, nodal involvement, estrogen and progesterone receptor content) from 596 patients recruitedat a comprehensive cancer center, we developed a prediction model which we validated in an independent cohort of 175patients recruited at a general hospital. Calculated at 3 and 4 years of follow-up, the discrimination indices were 0.716[confidence limits (CL) 0.641, 0.752] and 0.714 (CL 0.650, 0.750) for the training data, and 0.726 (CL 0.591, 0.769) and0.677 (CL 0.580, 0.745) for the testing data. Waiting for more effective approaches from genomic and proteomic studies, amodel based on consolidated pathobiological variables routinely assessed at relatively low costs may be considered as thereference for assessing the gain of new markers over traditional ones, thus substantially improving the conventional use ofprognostic criteria.
The International journal of biological markers 01/2008; 23(4):199-206. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Axillary dissection, an invasive procedure that may adversely affect quality of life, used to obtain prognostic information in breast cancer, is being supplanted by sentinel node biopsy. In older women with early breast cancer and no palpable axillary nodes, it may be safe to give no axillary treatment. We addressed this issue in a randomized trial comparing axillary dissection with no axillary dissection in older patients with T1N0 breast cancer.
From 1996 to 2000, 219 women, 65 to 80 years of age, with early breast cancer and clinically negative axillary nodes were randomized to conservative breast surgery with or without axillary dissection. Tamoxifen was prescribed to all patients for 5 years. The primary endpoints were axillary events in the no axillary dissection arm, comparison of overall mortality (by log rank test), breast cancer mortality, and breast events (by Gray test).
Considering a follow-up of 60 months, there were no significant differences in overall or breast cancer mortality, or crude cumulative incidence of breast events, between the 2 groups. Only 2 patients in the no axillary dissection arm (8 and 40 months after surgery) developed overt axillary involvement during follow-up.
Older patients with T1N0 breast cancer can be treated by conservative breast surgery and no axillary dissection without adversely affecting breast cancer mortality or overall survival. The very low cumulative incidence of axillary events suggests that even sentinel node biopsy is unnecessary in these patients. Axillary dissection should be reserved for the small proportion of patients who later develop overt axillary disease.
Annals of Surgery 08/2005; 242(1):1-6; discussion 7-9. DOI:10.1097/01.sla.0000167759.15670.14 · 8.33 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In 212 postmenopausal women with node-positive oestrogen receptor-positive (ER(LBA)) breast cancer subjected to radical surgery and adjuvant tamoxifen, the risk of 6-year relapse increased with increasing values of intratumoral vascular endothelial growth factor (VEGF) in patients whose tumours had a low/intermediate ER(LBA) content compared to patients with high-ER(LBA) tumours. These findings indicate that tumour progression, activated or sustained by high VEGF levels, may be counteracted in high-ER(LBA) cancers by tamoxifen, which in contrast fails to contrast the metastatic potential in low-ER(LBA) tumours.
British Journal of Cancer 08/2003; 89(2):268-70. DOI:10.1038/sj.bjc.6601060 · 4.84 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To analyze the time-dependent prognostic role of the investigated variables, considered, when appropriate, on a continuous scale, for the purpose of evaluating and describing the interrelationships between clinically relevant patient and tumor characteristics (age, size and histology, and estrogen receptor [ER] and progesterone receptor content) and the risk of new disease manifestation.
We applied a flexible statistical model to a case series of 1,793 patients with axillary lymph node-negative breast cancer with a minimal potential follow-up of 10 years. To avoid a potential confounding effect of adjuvant treatment, only patients given local-regional therapy until relapse were considered.
ER content and tumor size (adjusted for all the other covariates) showed a time-dependent relationship with the risk of new disease manifestations. In particular, ER content failed to show a prognostic effect within the first years of follow-up; thereafter, a positive association with risk of relapse was observed. For tumor size, within the first years of follow-up, the risk of relapse was directly related to size for only tumors up to 2.5 cm in diameter; thereafter, the impact on prognosis progressively decreased.
The availability of a long follow-up on a large breast cancer series, as well as the use of innovative statistical approaches, allowed us to explore the functional relation between steroid receptors and clinical outcome and to generate a hypothesis on the involvement of ER in favoring long-term metastasis development.
Journal of Clinical Oncology 08/2000; 18(14):2702-9. · 18.43 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Based on previous clinical experience indicating the tolerability and efficacy of high-dose cisplatin with glutathione protection in the treatment of advanced ovarian cancer, this study was undertaken to explore the efficacy and feasibility of an alternative high-dose, platinum-based approach including a combination of high-dose cisplatin plus carboplatin as induction chemotherapy of advanced ovarian carcinoma and intervention surgery. Fifty consecutive eligible patients with untreated stage III or IV epithelial ovarian cancer received 40 mg/m(2) cisplatin daily on days 1-4 and 160 mg/m(2) carboplatin on day 5. The cycle was repeated after 28 days. Patients received glutathione (2,500 mg) before each cisplatin or carboplatin administration and standard intravenous hydration. After 2 courses of induction chemotherapy, the patients underwent surgical reevaluation with debulking, when possible, followed by a further 3 cycles of 120 mg/m(2) cisplatin (i.e. 40 mg/m(2) daily for 3 consecutive days plus 600 mg/m(2) cyclophosphamide on day 3) except in instances of lack of response. All eligible patients were assessed for response and toxicity. The toxicity was moderate with lack of significant nephrotoxicity. Neurotoxicity and ototoxicity were acceptable and in no patient was treatment discontinued for those toxic effects. Myelotoxicity was somewhat more severe than that observed with our previous study with high-dose cisplatin and probably related to the addition of carboplatin. Of the 40 responsive patients, 23 (46%) had a pathological complete response and 4 (8%) had a clinical complete response (without second-look laparotomy). The efficacy of the present protocol was also documented by overall survival (median survival >48 months), which appeared to be better than expected with the current therapy in this group with advanced/bulky disease. The impressive efficacy suggests a possible contribution of reduced glutathione itself in improving the outcome, as supported by preclinical studies. The results of this study should be placed in context with current platinum-based therapy including paclitaxel.
[Show abstract][Hide abstract] ABSTRACT: In current clinical practice for breast cancer patients, estrogen (ER) and progesterone receptor (PgR) concentrations, quantified by the dextran-coated charcoal assay, are categorized by an arbitrary cutoff into a negative or positive status. However, although the results obtained with this approach are easy to interpret, such a representation could oversimplify the relationship between ER and PgR content and patient outcome and imply an assumption of monotonicity, which is generally expected but rarely proven. We evaluated the relationship between ER and PgR content (considered on a continuous scale) and clinical outcome, using a flexible statistical model, in a group of postmenopausal patients with N-positive operable tumors who were submitted to surgery and different adjuvant treatments (tamoxifen or CMF). Univariate analysis indicated that in the tamoxifen-treated group, ER level, number of metastatic nodes (pN) and age, but not PgR, were significant indicators of clinical outcome (p = 0.032, p = 0.021 and p = 0.029, respectively). Multivariate analysis indicated that in this group of patients there was no interaction between variables, and in the final model for disease-free survival (DFS) only ER and pN were retained with an overall predictive ability of the regression model of 0.723, as evaluated by Harrell's c. However, pN markedly contributed to the predictive ability of the model with respect to ER, since a marked decrease in Harrell's c statistic (c = 0.582) was observed when pN was removed from the model. In the CMF-treated group, only pN affected clinical outcome. When the estimated DFS curves obtained from the final Cox regression models were plotted according to four values of ER (in the tamoxifen-treated group) or three values of pN (in the CMF-treated group) we observed that in the tamoxifen-treated group patients with an ER concentration equal to 0 fmol/mg cytosol protein had the worst prognosis, whereas a marked improvement of the expected DFS was observed for patients with a low but detectable ER level (generally classified as ER-negative because falling below the conventional cutoff value of 10 fmol/mg cytosol protein). Our results seem to suggest that the use of steroid receptor concentrations on a continuous scale, instead of dichotomous "status", is to be preferred in the choice of adequate therapeutic strategies.
The International journal of biological markers 01/1999; 14(2):60-7. · 1.37 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We compared oestrogen receptor (ER) and progesterone receptor (PgR) profiles between primary and corresponding contralateral breast cancer (CBC) to investigate whether CBC should be considered relapse of a primary or as a feature of the multicentric origin of breast cancer. We adjusted for patient age, menopausal status, histology and adjuvant therapy. In spite of the general application of a cut-off value to dichotomise ER and PgR, we considered them as continuous variables. Moreover, we considered as synchronous cancers only simultaneously occurring lesions. For 399 patients, ER and PgR receptor levels in primary and CBC did not differ significantly, but were significantly correlated within the same patient. The correlation was higher for synchronous than for metachronous lesions when considering ER, but not PgR. The correlation between ER and PgR levels in the same tumour (primary or CBC) appeared stronger than the correlation of either receptor type (ER or PgR) between primary and CBC. Age, histology and adjuvant treatment affected ER concentration, whereas age, menopausal status and histology affected PgR concentration. The analysis indicated that primary and CBC tend to be characterised by a similar steroid receptor profile. The finding may support the hypothesis of CBC as a second primary arising in a common predisposing milieu, rather than a primary-dependent contralateral lesion. In this light, the clinical management of patients with a bilateral breast cancer should be similar to that of a unilateral breast cancer.
European Journal of Cancer 06/1998; 34(6):825-30. DOI:10.1016/S0959-8049(97)10121-6 · 5.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To better understand the prognostic relevance of change in steroid receptor status, during the clinical course of breast cancer, we analysed the variation of estrogen and progesterone receptor (ER, PgR) status in a series of 532 primary tumors and metachronous accessible recurrences in individual patients. A more consistent variation was observed in patients with a receptor-positive primary (ER(+) or PgR(+)) than in those with a receptor-negative tumor (ER(-) or PgR(-)). Forty-four percent of PgR(+) and 24% of ER(+) tumors became negative, whereas only 20% of ER(-) or PgR(-) became positive. The changes were independent of tumor stage and menopausal status. However, steroid receptor variation appeared to be related to the interval between the primary tumor and relapse. In fact, the changes from ER(+) to ER(-) were more frequent in patients with a disease-free survival of less than 1 year, whereas changes from ER(-) to ER(+) occurred more often in patients with a disease-free survival of more than 3 years. Moreover, we observed a decrease in the number of ER(+) tumors following hormone treatment and a decrease in ER(-) tumors following chemotherapy. However, such variations did not reach statistical significance. Irrespective of the type of adjuvant therapy, the presence of at least one receptor (in particular, PgR) in the metachronous lesion was correlated with a long median time to relapse and to death. Our results confirmed the predictive relevance of receptor status of the primary lesion on relapse and survival and suggest the predictive relevance of receptor status of the metachronous lesion on post-relapse survival.
International Journal of Oncology 05/1996; 8(5):997-1002. DOI:10.3892/ijo.8.5.997 · 3.03 Impact Factor