-
Journal of Translational Medicine Jul 2013The aim of the present study was to investigate within ovarian carcinoma and normal ovarian biopsies the gene expression of multiple secretoglobin family members...
BACKGROUND
The aim of the present study was to investigate within ovarian carcinoma and normal ovarian biopsies the gene expression of multiple secretoglobin family members relative to mammaglobin B, which we previously reported as a promising novel ovarian carcinoma prognostic marker.
METHODS
Using quantitative real-time Reverse Transcription PCR we tested 53 ovarian carcinoma and 30 normal ovaries for the expression of 8 genes belonging to the secretoglobin family: mammaglobin A, lipophilin A, lipophilin B, uteroglobin, HIN-1, UGRP-1, RYD5 and IIS. Next, we decided to expand the LipB gene expression analysis to a further 48 ovarian carcinoma samples, for a total of 101 tumor tissues of various histologies and to study its protein expression by immunohistochemistry in formalin-fixed paraffin-embedded tumors and normal ovaries. Finally, we correlated lipophilin B gene and protein expression to conventional patient clinico-pathological features and outcome.
RESULTS
We found significant mammaglobin A, lipophilin A, lipophilin B and RYD5 gene overexpression in ovarian carcinomas compared to normal ovaries. Lipophilin B mRNA showed a higher presence in tumors (75.4%) compared to normal ovaries (16.6%) and the most significant correlation with mammaglobin B mRNA (rs =0.77, p < 0.001). By immunohistochemical analysis, we showed higher lipophilin B expression in the cytoplasm of tumor cells compared to normal ovaries (p < 0.001). Moreover, lipophilin B gene overexpression was significantly associated with serous histology (serous vs clear cell p = 0.027; serous vs undifferentiated p = 0.007) and lower tumor grade (p = 0.02). Lower LipB mRNA levels (low versus high tertiles) were associated to a shorter progression-free (p = 0.03, HR = 2.2) and disease-free survival (p = 0.02, HR = 2.5) by univariate survival analysis and, importantly, they remain an independent prognostic marker for decreased disease-free (p = 0.001, HR = 3.9) and progression-free survival (p = 0.004, HR = 2.8) in multivariate Cox regression analysis.
CONCLUSIONS
The present study represents the first quantitative evaluation of secretoglobin gene expression in normal and neoplastic ovarian tissues. Our results demonstrate lipophilin B gene and protein upregulation in ovarian carcinoma compared to normal ovary. Moreover, lipophilin B gene overexpression correlates with a less aggressive tumor phenotype and represents a novel ovarian carcinoma prognostic factor.
Topics: Aged; Biomarkers, Tumor; Disease-Free Survival; Female; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Immunohistochemistry; Middle Aged; Ovarian Neoplasms; Ovary; Phenotype; Prognosis; Real-Time Polymerase Chain Reaction; Secretoglobins; Treatment Outcome; Up-Regulation
PubMed: 23819652
DOI: 10.1186/1479-5876-11-162 -
Pathology Oncology Research : POR Apr 2018Estrogen and progesterone receptors are possible markers for suggesting a mammary origin of metastatic carcinoma, but are useless in cases of triple negative breast...
Estrogen and progesterone receptors are possible markers for suggesting a mammary origin of metastatic carcinoma, but are useless in cases of triple negative breast cancers (TNBC). Five other potential markers of breast origin were investigated on tissue microarrays in a series of TNBCs showing keratin 5 expression, consistent with a basal-like phenotype. GATA-3 staining was observed in 82 of 115 triple negative cases (71.3%) including 23 cases with >5% staining. Mammaglobin staining was detected in 30 cases (26.0%) including 12 with >5% staining. GCDFP-15 was seen in 23 cases (20.0%) including 9 with >5% staining. NY-BR-1 positivity was present in 7 cases (6.0%) including 3 patients with >5% staining. BCA-225 staining was observed in 74 cases (64.3%); however this latter marker lacks also specificity owing to the reported widespread staining in other malignancies. GATA-3, mammaglobin and GCDFP-15 coexpression was seen in one case (0.9%), whereas GATA-3 and mammaglobin or mammaglobin and GCDFP-15 coexpression was present in 2 and 2 cases (1.7%), respectively. Using at least 5% staining as cut-off, the expression of any of the last 4 markers was 34.7%. The expression of GATA-3, mammaglobin, GCDFP-15 and NY-BR-1 is lower in TNBC-s than in breast carcinomas in general, and this may be even lower in basal-like carcinomas. Although these markers are not fully specific, by using them, a subset of basal-like TNBC-s can be identified as of mammary origin. However, a substantial proportion will not show any staining with any of these markers.
Topics: Antigens, Neoplasm; Biomarkers, Tumor; Carcinoma; Carrier Proteins; Female; GABA Plasma Membrane Transport Proteins; Glycoproteins; Humans; Immunohistochemistry; Keratin-5; Mammaglobin A; Membrane Transport Proteins; Triple Negative Breast Neoplasms
PubMed: 28470571
DOI: 10.1007/s12253-017-0246-y -
International Journal of Clinical and... 2009Identification of metastasis and occult micrometastases of breast cancer demands sensitive and specific diagnostic markers. In this study, we assessed the utility of a...
Identification of metastasis and occult micrometastases of breast cancer demands sensitive and specific diagnostic markers. In this study, we assessed the utility of a mouse monoclonal antibody to human mammaglobin for one such purpose. Immunohistochemical stains were performed on paraffin-embedded sections from a total of 284 cases, which consisted of primary breast invasive carcinomas (41 cases) with matched metastases to ipsilateral axillary lymph nodes, metastatic breast carcinoma to liver (1 case) and kidney (1 case), non-breast neoplasms (161 cases), and normal human tissues (39 cases). The results showed 31 of the 41 cases of primary breast cancer with axillary lymph node metastases were positive for mammaglobin (76%). In the meantime, we documented expression of mammaglobin in occasional cases of endometrial carcinoma (17%). Our data further validated that mammaglobin is a valuable diagnostic marker for metastatic carcinoma of breast origin, although endometrial carcinoma should be considered as a major differential diagnosis.
PubMed: 19158935
DOI: No ID Found -
Annals of Oncology : Official Journal... Mar 2002The aim of this study was: (i) to evaluate the sensitivity and specificity of mammaglobin as a reverse transcriptase polymerase chain reaction (RT-PCR) marker of breast... (Comparative Study)
Comparative Study
BACKGROUND
The aim of this study was: (i) to evaluate the sensitivity and specificity of mammaglobin as a reverse transcriptase polymerase chain reaction (RT-PCR) marker of breast cancer cells; (ii) to determine the incidence of tumor cell contamination of hematopoietic samples from patients with breast cancer.
MATERIALS AND METHODS
A nested RT-PCR assay for mammaglobin was developed. Sensitivity was determined by serial dilution assays with breast cancer cell lines, human breast cancers and normal breast tissue. Specificity was evaluated in hematopoietic samples from healthy volunteers and patients with hematological malignancies or solid tumors other than breast cancer.
RESULTS
The mammaglobin transcript was detected in all 15 breast cancers, one benign breast tumor and five normal breast tissues studied, as well as in three breast cancer cell lines, in dilutions as low as 10(-8). The transcript was not detected in any of 47 peripheral blood samples, 15 bone marrow aspirates and 28 peripheral blood progenitor cell samples from the three control populations. Mammaglobin mRNA was detected in 19 of 78 peripheral blood samples from patients with breast cancer starting systemic chemotherapy, as well as in five of 30 repeat samples collected before the fourth cycle of treatment. The transcript was also present in six of seven bone marrow aspirates from patients with metastatic disease, two of five with loco-regional disease, but not in the aspirate of two patients with thrombocytopenia and a previous history of breast cancer.
CONCLUSIONS
Human mammaglobin mRNA is a sensitive and specific marker of breast cancer cells and should be further studied as a molecular marker of tumor cell contamination of hematopoietic tissues.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Female; Humans; Mammaglobin A; Middle Aged; Neoplasm Proteins; Neoplastic Cells, Circulating; RNA, Messenger; RNA, Neoplasm; Reverse Transcriptase Polymerase Chain Reaction; Sensitivity and Specificity; Tumor Cells, Cultured; Uteroglobin
PubMed: 11996474
DOI: 10.1093/annonc/mdf107 -
Laboratory Investigation; a Journal of... Jul 2000Various molecular markers have been used for the detection of circulating breast cancer cells in blood by reverse transcriptase-polymerase chain reaction (RT-PCR). Using... (Comparative Study)
Comparative Study
Various molecular markers have been used for the detection of circulating breast cancer cells in blood by reverse transcriptase-polymerase chain reaction (RT-PCR). Using nested RT-PCR, we compared the specificity and sensitivity of human mammaglobin (hMAM), epidermal-growth-factor receptor (EGF-R), and cytokeratin 19 (CK-19) expression as markers for circulating carcinoma cells in the peripheral blood of patients with breast cancer. Blood samples from 12 patients with ductal carcinoma in situ, 133 patients with invasive breast cancer, 20 patients with hematological malignancies, 31 healthy volunteers, and tumor tissues from 40 patients with invasive breast cancer were screened for mRNA encoding hMAM, EGF-R, or CK-19 by nested RT-PCR. In all breast cancer tissues, mRNA for hMAM, EGF-R, and CK-19 was detectable. In blood samples from patients with invasive breast cancer, 11 (8%), 13 (10%), and 64 (48%) were positive for mRNA encoding hMAM, EGF-R, or CK-19, respectively. Blood samples from none of the healthy volunteers and patients with hematological disorders were positive for hMAM, while CK-19 mRNA was found in the blood of 12 (39%) healthy volunteers and transcripts for EGF-R and CK-19 were detectable in 5 (25%) and 2 (10%), respectively, of the patients with hematological malignancies. Only hMAM mRNA expression in blood correlated with clinical parameters such as nodal status, metastasis, and CA 15-3 serum levels. In summary, hMAM transcripts detectable in blood by RT-PCR represent the most specific molecular marker for hematogenous spread of breast cancer cells. With the nested RT-PCR method, aberrant EGF-R mRNA expression might occasionally be found in hematological malignancies, whereas CK-19 mRNA expression proved to be rather nonspecific. The prognostic value of hMAM RT-PCR-based tumor cell detection in peripheral blood should be further tested and validated in prospective studies.
Topics: Adult; Aged; Biomarkers, Tumor; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Ductal, Breast; ErbB Receptors; Female; Gene Expression; Hematologic Neoplasms; Humans; Keratins; Mammaglobin A; Middle Aged; Neoplasm Invasiveness; Neoplasm Proteins; Tumor Cells, Cultured; Uteroglobin
PubMed: 10908152
DOI: 10.1038/labinvest.3780112 -
Archives of Pathology & Laboratory... Oct 2003Organ specificity is a desirable property of a tumor marker, especially in metastatic adenocarcinomas of unknown primary origin. Mammaglobin, a mammary-specific member...
CONTEXT
Organ specificity is a desirable property of a tumor marker, especially in metastatic adenocarcinomas of unknown primary origin. Mammaglobin, a mammary-specific member of the uteroglobin family, is known to be overexpressed in human breast cancer.
OBJECTIVE
We investigated mammaglobin A expression in metastatic carcinomas of lymph nodes from the breast and various other organs and its usefulness in identifying metastatic carcinoma of the breast. For comparative purposes, we also investigated BRST-1 and BRST-2 expression.
DESIGN
We produced recombinant mammaglobin and polyclonal antimammaglobin antibodies. Mammaglobin expression was analyzed by immunohistochemical staining using a tissue microarray and by reverse transcription-polymerase chain reaction in 210 carcinomas, including those of the breast (n = 70), lung (n = 30), stomach (n = 30), colorectum (n = 25), hepatobiliary tract (n = 20), urinary tract (n = 10), thyroid gland (n = 10), ovary and endometrium (n = 10), and salivary gland (n = 5).
RESULTS
Mammaglobin expression was observed in 59 cases (84.3%) of breast cancer and in 21 cases (15.0%) of nonbreast cancer. The BRST-1 and BRST-2 expression rates were 75.7% and 44.3% in breast cancer and 26.4% and 2.1% in nonbreast cancer, respectively. Mammaglobin is superior to BRST-1 for both specificity and sensitivity and is superior to BRST-2 for sensitivity.
CONCLUSION
Our data suggest that mammaglobin is one of the first relatively mammary-specific and mammary-sensitive markers. Mammaglobin and BRST-2 appear to represent useful markers for breast cancer and should be used as a component of panels evaluating tumors of unknown primary sites.
Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Female; Gene Expression; Humans; Immunohistochemistry; Lymph Nodes; Lymphatic Metastasis; Mammaglobin A; Neoplasm Proteins; Reverse Transcriptase Polymerase Chain Reaction; Uteroglobin
PubMed: 14521461
DOI: 10.5858/2003-127-1330-MEILNI -
FEBS Open Bio Oct 2022Overexpression of human epidermal growth factor receptor 2 (HER2) in various cancers is correlated with poor patient survival. Trastuzumab, a recombinant humanized...
Overexpression of human epidermal growth factor receptor 2 (HER2) in various cancers is correlated with poor patient survival. Trastuzumab, a recombinant humanized monoclonal antibody against HER2, has been considered to be a first-line therapy for HER2-positive breast cancer patients, but its usefulness is limited by the development of resistance. In this study, we established resistant cells by long-term treatment with trastuzumab. These cells showed higher proliferation, invasion, and migration abilities than the wild-type cells. Mammaglobin 1 (MGB1), cyclin D1, E1, A2, and phosphorylated NF-κB (p-p65) were upregulated in resistant cells. These proteins regulate cell proliferation, migration, and invasion of resistant cells. Depletion of MGB1 decreased cyclin and p-p65 expression. Cyclin D1 and A2, but not E1 expression, were affected by p-p65 downregulation. In summary, our results indicate that MGB1 expression is increased in breast cancer cells that have gained resistance to trastuzumab, and suggest that MGB1 promotes aggressiveness through cyclin and NF-κB regulation.
Topics: Breast Neoplasms; Cell Line, Tumor; Cyclin D1; Female; Humans; Mammaglobin A; NF-kappa B; Trastuzumab
PubMed: 35945910
DOI: 10.1002/2211-5463.13468 -
Genetics and Molecular Research : GMR Nov 2012Different treatment outcomes and prognoses in patients with breast cancer can be observed with similar clinical predictors; this is because the biology of breast cancer...
Different treatment outcomes and prognoses in patients with breast cancer can be observed with similar clinical predictors; this is because the biology of breast cancer is complex and heterogenous, involving multiple unknown contributing factors. We looked for plasma human mammaglobin (hMAM) mRNA by RT-PCR in 82 Korean patients with breast cancer to determine if there is an association between the presence of plasma hMAM mRNA in these patients and known prognostic factors. The prognostic usefulness of detection of plasma hMAM mRNA expression in these patients was also evaluated by determining overall survival and event-free survival. A significant difference was observed in the rate of positivity of plasma hMAM mRNA between the early stages of cancer (stages I-II, 23.4%) and advanced stages (stages III-IV, 82.9%). The expression rates of estrogen receptor, progesterone receptor, and HER-2/neu in the breast tissue of these patients, by immunohistochemistry, were 69.5, 75.6, and 20.7%, respectively. In the univariate analysis, plasma hMAM expression was significantly correlated with high histological and nuclear grades, nodal metastasis, and negative estrogen receptor and progesterone receptor status. Patients negative for plasma hMAM mRNA had significantly higher rates of event-free survival compared to the patients positive for plasma hMAM mRNA. However, no significant association with overall survival was observed for expression of plasma hMAM mRNA (P = 0.16). Qualitative detection of plasma hMAM mRNA appears to be associated with unfavorable prognostic factors and lower rates of event-free survival in patients with breast cancer.
Topics: Adult; Aged; Aged, 80 and over; Breast Neoplasms; Disease-Free Survival; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mammaglobin A; Middle Aged; RNA, Messenger
PubMed: 23212340
DOI: 10.4238/2012.November.28.2 -
Human Pathology Oct 2013Mammary analogue secretory carcinoma is a recently described salivary gland neoplasm defined by ETV6-NTRK3 gene fusion. Mammary analogue secretory carcinoma's morphology...
Mammary analogue secretory carcinoma is a recently described salivary gland neoplasm defined by ETV6-NTRK3 gene fusion. Mammary analogue secretory carcinoma's morphology is not entirely specific and overlaps with other salivary gland tumors. Documenting ETV6 rearrangement is confirmatory, but most laboratories are not equipped to perform this test. As mammary analogue secretory carcinomas are positive for mammaglobin, immunohistochemistry could potentially replace molecular testing as a confirmatory test, but the specificity of mammaglobin has not been evaluated across a large and diverse group of salivary gland tumors. One hundred thirty-one salivary gland neoplasms were evaluated by routine microscopy, mammaglobin immunohistochemistry, and ETV6 break-apart fluorescent in situ hybridization. The cases included 15 mammary analogue secretory carcinomas, 44 adenoid cystic carcinomas, 33 pleomorphic adenomas, 18 mucoepidermoid carcinomas, 10 acinic cell carcinomas, 4 adenocarcinomas not otherwise specified, 3 polymorphous low-grade adenocarcinomas, 3 salivary duct carcinomas, and 1 low-grade cribriform cystadenocarcinoma. All 15 mammary analogue secretory carcinomas harbored the ETV6 translocation and were strongly mammaglobin positive. None of the 116 other tumors carried the ETV6 translocation; however, mammaglobin staining was present in 1 (100%) of 1 low-grade cribriform cystadenocarcinoma, 2 (67%) of 3 polymorphous low-grade adenocarcinomas, 2 (67%) of 3 salivary duct carcinomas, 2 (11%) of 18 mucoepidermoid carcinomas, and 2 (6%) of 33 pleomorphic adenomas. Mammaglobin is highly sensitive for mammary analogue secretory carcinoma, but immunostaining can occur in a variety of tumors that do not harbor the ETV6 translocation. Strategic use of mammaglobin immunostaining has a role in the differential diagnosis of salivary gland neoplasms, but it should not be indiscriminately used as a confirmatory test for mammary analogue secretory carcinoma.
Topics: Adenoma, Pleomorphic; Biomarkers, Tumor; Breast Neoplasms; Carcinoma; Carcinoma, Acinar Cell; Carcinoma, Adenoid Cystic; Carcinoma, Mucoepidermoid; Cystadenocarcinoma; Female; Humans; Immunohistochemistry; Mammaglobin A; Oncogene Proteins, Fusion; Salivary Gland Neoplasms; Tissue Array Analysis; Translocation, Genetic
PubMed: 23773480
DOI: 10.1016/j.humpath.2013.03.017 -
Oncoimmunology Jun 2013Regulatory T cells (Tregs) play an important role in controlling antitumor T-cell responses and hence represent a considerable obstacle for cancer immunotherapy. The...
Regulatory T cells (Tregs) play an important role in controlling antitumor T-cell responses and hence represent a considerable obstacle for cancer immunotherapy. The abundance of specific Treg populations in cancer patients has been poorly analyzed so far. Here, we demonstrate that in breast cancer patients, Tregs often control spontaneous effector memory T-cell responses against mammaglobin, a common breast tissue-associated antigen that is overexpressed by breast carcinoma. Using functional assays, we identified a HLA-DRB1*04:01- and HLA-DRB1*07:01-restricted epitope of mammaglobin (mam) that was frequently recognized by Tregs isolated from breast cancer patients. Using mam-labeled HLA Class II tetramers, we quantified mammaglobin-specific Tregs and CD4 conventional T (Tcon) cells in breast carcinoma patients as well as in healthy individuals. Both mammaglobin-specific Tregs and Tcon cells were expanded in breast cancer patients, each constituting approximately 0.2% of their respective cell subpopulations. Conversely, mammaglobin-specific Tregs and CD4 Tcon cells were rare in healthy individuals (0.07%). Thus, we provide here for the first time evidence supporting the expansion of breast tissue-specific Tregs and CD4 Tcon cells in breast cancer patients. In addition, we substantiate the potential implications of breast tissue-specific Tregs in the suppression of antitumor immune responses in breast cancer patients. The HLA Class II tetramers used in this study may constitute a valuable tool to elucidate the role of antigen-specific Tregs in breast cancer immunity and to monitor breast cancer-specific CD4 T cells.
PubMed: 23894725
DOI: 10.4161/onci.24962