[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.
[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. · 1.71 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;
[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. 01/2012; 2012:984346.
[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.
[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. · 1.59 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. · 6.33 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. · 5.08 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. · 18.04 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: 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. · 5.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: DNA topoisomerases, nuclear enzymes that regulate DNA topology, are recognized as the primary targets of effective anti-tumor drugs. These enzymes may also have a role in the repair of DNA damage induced by alkylating agents and platinum compounds; therefore, their expression may be a determinant of tumor response to chemotherapy. Our study was undertaken in an attempt to establish a correlation between the enzyme expression and response of ovarian cancer to cisplatin-based chemotherapy. The expression of topoisomerase I, II alpha and II beta genes was assessed by RNase protection assay in tumor specimens obtained from 37 untreated patients with advanced epithelial ovarian cancer at initial surgery and from 13 pre-treated patients at subsequent laparotomy. The expression levels were compared with those found in 5 specimens from benign ovarian tissue and 5 specimens from normal ovarian tissue. The expression levels in untreated patients were used to establish a correlation with response to high-dose cisplatin therapy. A significant intertumor variability of mRNA expression was noted for all the genes examined. However, a comparison of median values indicated a remarkable increase of expression in malignant tumors over benign or normal tissues only for topoisomerase II alpha. This change is not related to alterations or amplification of topoisomerase II alpha gene. Interestingly, a correlation was found between tumor response to chemotherapy and the expression level of the isoform alpha (but not of topoisomerase II beta and topoisomerase I). The observed correlation suggests a contribution of the enzyme in determining tumor sensitivity. Alternatively, increased expression levels of the alpha isoenzyme gene in responsive tumors might reflect higher fractions of proliferating tumor cells that may be more drug-sensitive than resting cells.
International Journal of Cancer 09/1996; 67(4):479-84. · 6.20 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. · 2.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The p53 protein is a multifunctional transcriptional regulator involved in cellular response to DNA damage and has been implicated as a putative determinant of sensitivity of tumor cells to cytotoxic agents. Since the p53 gene becomes inactivated in over one-half of advanced ovarian carcinoma, in this study we have examined the relationships between p53 gene alterations, p53 immunoreactivity, and response to cisplatin-based chemotherapy in ovarian cancer patients. All patients had advanced (FIGO stage III or IV) ovarian carcinoma and, with one exception, were untreated at the time of collection of tumor specimens. After initial debulking surgery, patients received high-dose cisplatin therapy. Tumor samples were analyzed for p53 gene mutations and for p53 protein accumulation, and the findings were correlated with tumor responsiveness. Of the 33 tumors examined, p53 gene mutations were found in 20 cases, including 15 missense mutations, 2 deletions, 2 nonsense mutations, and a base substitution at splice site. Twenty tumors showed positive immunostaining for p53. Only missense mutations were associated with positive immunostaining. In addition, p53 overexpression was detected in five tumors in the absence of mutations. Most (12 of 14) of the missense mutations associated with p53 protein stabilization were found refractory to therapy, as well as tumors overexpressing wild-type p53 (4 of 5). A significant correlation has been found between p53 accumulation, type of mutation (i.e., missense mutations), and pathological response to cisplatin-based therapy. In conclusion, the present results are consistent with a role of p53 as a determinant of chemosensitivity of ovarian carcinoma.
Cancer Research 03/1996; 56(4):689-93. · 8.65 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of the present study was to determine the activity of a combined regimen of mitoxantrone (DHAD) and ifosfamide (IFO) and identify clinical and biological factors with prognostic importance for the second-line treatment of ovarian cancer. The following factors were investigated for their prognostic importance: age, disease sites, platinum responsiveness, histological grade, the presence of clinically/radiologically detectable versus not detectable disease, residual disease volume after first surgery, p53 protein, c-erbB-2 oncoprotein and laminin receptor. 72 patients entered the trial. DHAD and IFO therapy led to a 15% response rate among the 47 cases with clinically/radiologically detectable disease (1 complete and 6 partial responses), with a median response duration of 4 months. The response rate was significantly different according to platinum responsiveness (4% objective responses in platinum-resistant versus 27% in platinum-sensitive disease). The time to treatment failure (TTF) and overall survival (OS) were affected by the presence of clinically detectable disease at study entry (median TTF 4 months in the presence of clinically/radiologically detectable disease versus 9 months if the disease was not similarly detectable, P = 0.02; median OS 10 months versus 21 months, P = 0.01). Initially overexpressed in only a few tumours, the c-erbB-2 oncoprotein became overexpressed in 36% of platinum-resistant tumours; this modulation did not occur in platinum-sensitive tumours. Furthermore, laminin receptor was expressed in 77% of platinum-sensitive versus 39% of platinum-resistant patients. There were no differences in p53 protein expression according to drug responsiveness.
European Journal of Cancer 01/1996; 31A(13-14):2248-54. · 5.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Both mitoxantrone (DHAD) and ifosfamide (IFO) have given promising results when administered as single agents in advanced ovarian cancer pretreated with platinum compounds. The aim of this I.T.M.O. group pilot trial was to evaluate, in a selected population of ovarian cancer patients, the efficacy and tolerability of the following intensive second-line regimen: DHAD, 12 mg/m2 i.v., day 1; IFO, 4,000 mg/m2 i.v., days 1 and 2; Mesna, 800 mg/m2 i.v. t.i.d., days 1 and 2. Filgrastim (5 micrograms/kg/day i.m.) was given from day 6 to day 19 to reduce the expected neutropenia. Cycles were repeated every 21 days.
Nineteen platinum-pretreated patients were enrolled and 14 were evaluated for tumor response; the disease of 5 patients was not measurable clinically or radiologically.
Seven responses were observed (3 CRs), with a median response duration of 5 months. The median time to treatment failure and overall survival for all 19 patients was respectively 8 and 13 months. Anemia was observed in all of the treated patients (grade 3-4 in 9 cases). Only 6 of the 19 patients ended the five planned cycles of chemotherapy without any delay.
Although DHAD plus IFO induced a considerable number of objective responses, the limited response duration time to treatment failure, and overall survival as well as the reported side effects suggest that this is not a recommended regimen for the palliative treatment of ovarian cancer patients undergoing second-line chemotherapy.