transforming-growth-factor-alpha and Carcinoma--Intraductal--Noninfiltrating

A pilot study of a novel translational research method to simultaneously assay multiple molecular markers and DNA in fine-needle aspirates (FNA) of mammographically detected breast lesions is described. Specimen mammography-guided 20-gauge FNAs obtained from 86 lesions and 22 areas of normal tissue were analyzed by multiparameter flow cytometry for DNA content, her2/neu, transforming growth factor alpha (TGF alpha), and the epithelial marker cytokeratin (CK) simultaneously. Epithelial cell her2/neu positivity was detected in 12 of 44 (27%) of invasive ductal carcinomas and 3 of 9 (33%) ductal carcinoma in situ (DCIS), 10 of 30 (33%) benign lesions, and 4 of 22 (18%) normal tissue aspirates. All lesions and normal tissue showed a similar positive rate for TGFalpha ranging from 61 to 76%. The CK(+)TGF alpha(-)her2/neu(+) immunophenotype was more frequently positive in aneuploid tumors (22%) than all other lesions (7%) (P < 0.05). Specimen mammography-guided FNAs provide fresh cells for flow cytometric multiple marker analysis and immunophenotyping of clinically occult breast lesions and normal tissue.

Topics: Adult; Aged; Aged, 80 and over; Aneuploidy; Biomarkers, Tumor; Biopsy, Needle; Breast; Breast Neoplasms; Carcinoma; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; Diploidy; DNA; Female; Flow Cytometry; Humans; Immunophenotyping; Keratins; Mammography; Middle Aged; Pilot Projects; Receptor, ErbB-2; Transforming Growth Factor alpha

Localization of growth factors such as transforming growth factor alpha (TGF-alpha) and beta1 (TGF-beta1), insulin-like growth factor 1 (IGF-1), and epidermal growth factor receptor (EGFR) in breast cancer tissue is controversial. We immunohistochemically investigated expression patterns of these growth factors and EGFR along with estrogen receptor (ER) status in 36 breast carcinomas (21 invasive ductal, 11 invasive lobular, 4 noninvasive ductal) and compared the results with those found in 10 fibroadenomas. Twenty-four of 36 carcinomas and all of the 10 fibroadenomas showed positivity for ER. TGF-alpha was immunoreactive in all of the carcinomas and fibroadenomas. TGF-beta1 was negative in all of the invasive ductal carcinomas and positive in all of the fibroadenomas and in five lobular carcinomas. EGFR was regularly expressed preferentially in the myoepithelial cells of mammary ducts in the fibroadenomas and in nontumorous glands. Six of the 36 carcinomas were positive for EGFR. Those tumors were negative for ER (P < .001). There was IGF-1 expression in all of the cases of carcinoma and fibroadenoma. We conclude that TGF-alpha is expressed abundantly in invasive and intraductal breast carcinomas and in fibroadenomas. EGFR expression significantly correlates with negative ER status in breast carcinoma. In breast carcinoma, IGF-1 is broadly expressed by the tumor as well as by stromal cells and might act as a growth stimulator in endocrine, paracrine, and autocrine manners.

Topics: Adenocarcinoma; Adult; Aged; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, Noninfiltrating; Carcinoma, Lobular; ErbB Receptors; Female; Fibroadenoma; Humans; Immunohistochemistry; Insulin-Like Growth Factor I; Middle Aged; Transforming Growth Factor alpha; Transforming Growth Factor beta

In the last decade we have come to understand that the growth of cancer cells in general and of breast cancer in particular depends, in many cases, upon growth factors that will bind to and activate their receptors. One of these growth factor receptors is the erbB-2 protein which plays an important role in the prognosis of breast cancer and is overexpressed in nearly 30% of human breast cancer patients. While evidence accumulates to support the relationship between erbB-2 overexpression and poor overall survival in breast cancer, understanding of the biological consequence(s) of erbB-2 overexpression remains elusive. Our recent discovery of the gp30 has allowed us to identify a number of related but distinct biological endpoints which appear responsive to signal transduction through the erbB-2 receptor. These endpoints of growth, invasiveness, and differententiation te have clear implications for the emergence, maintenance and/or control of malignancy, and represent established endpoints in the assessment of malignant progression in breast cancer. We have shown that gp30 induces a biphasic growth effect on cells with erbB-2 over-expression. We have recently determined the protein sequence of gp30 and cloned its full length cDNA sequence. We have also cloned two additional forms to the ligand, that are believed to be different isoforms. We are currently expressing the different forms in order to determine their biological effects. To elucidate the cellular mechanisms underlying cell growth inhibition by gp30, we tested the effect of this ligand on cell growth and differentiation of the human breast cancer cells which overexpress erbB-2 and cells which express low levels of this protooncogene.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenocarcinoma; Breast Neoplasms; Cadherins; Carcinoma, Intraductal, Noninfiltrating; Cell Differentiation; Cell Division; Chemotaxis; Cloning, Molecular; Disease Progression; Endocytosis; Gene Expression Regulation, Neoplastic; Glycoproteins; Humans; Neoplasm Invasiveness; Neoplasm Proteins; Phosphorylation; Protein Processing, Post-Translational; Receptor, ErbB-2; Recombinant Fusion Proteins; Transcription Factor AP-1; Transforming Growth Factor alpha; Tumor Cells, Cultured

Transforming growth factor alpha (TGF alpha) and Transforming growth factor beta-1 (TGF-beta 1) are growth regulatory for breast cancer cell lines in vitro and several studies have suggested that levels of the receptor for TGF alpha, the epidermal growth factor (EGFR) in tumour biopsies predict relapse and survival. We have examined the prognostic significance of TGF alpha, TGF-beta 1 and EGFR mRNA expression in a series of patients with primary breast cancer with a median follow up period of 60 months. In 167 patients the expression of TGF-beta 1 was inversely correlated with node status (P = 0.065) but not ER status, tumour size or menopausal status. Patients with high levels of TGF-beta 1 had a longer disease free interval with a significantly longer probability of survival at 80 months although the overall relapse free survival was not increased. EGFR mRNA expression was measured in 106 patients and was inversely correlated with ER status (P = 0.018). EGFR levels did not predict for early relapse or survival. TGF alpha mRNA levels were measured in 104 patients, no correlation was seen tumour size, node status, Er status, or clinical outcome.

Topics: Adenocarcinoma, Mucinous; Adult; Aged; Aged, 80 and over; Breast Neoplasms; Carcinoma; Carcinoma, Intraductal, Noninfiltrating; ErbB Receptors; Female; Follow-Up Studies; Humans; Immunoblotting; Middle Aged; Prognosis; RNA, Messenger; Transcription, Genetic; Transforming Growth Factor alpha; Transforming Growth Factor beta; Transforming Growth Factors

TGF alpha and beta expression was examined using rabbit polyclonal antibodies and immunohistochemistry on a series of 195 breast carcinomas. TGF alpha immunoreactivity was observed in all but nine of the tumours, with over 50 per cent staining strongly. The polyclonal TGF alpha antibody (CIM1), when compared with a commercially available mouse monoclonal TGF alpha antibody used on the same sections, gave a good correlation (r = 0.52, P < 0.001). Both TGF alpha antibodies produced a granular cytoplasmic staining pattern, that with CIM1 being coarser, suggestive of binding to an aggregated protein or organelle. Eighty-one per cent of tumours stained with the TGF beta antibody, 35 per cent strongly. There was significant co-expression of TGF alpha and TGF beta (P < 0.001). However, they were not found to be useful prognostic indicators, lacking any significant correlation with histological classification, tumour size, nodal status, oestrogen receptor status, S-phase fraction, or overall survival over a 9-12 year period. The expression of these growth factors in most breast carcinomas suggests that they have important biological roles, but the exact nature of these roles remains unclear at the moment.

Topics: Adult; Aged; Breast Neoplasms; Carcinoma, Intraductal, Noninfiltrating; Female; Humans; Immunoenzyme Techniques; Middle Aged; Prognosis; Transforming Growth Factor alpha; Transforming Growth Factor beta

To determine at what stage there is increased expression of transforming growth factor alpha (TGF alpha) in preneoplastic diseases of the breast and to determine if this would assist in the histological diagnosis of different intraduct epithelial proliferations.. Specimens were retrieved from the archives of 17 cases of ductal hyperplasia, six cases of atypical ductal hyperplasia and 13 cases of ductal carcinoma in situ together with 12 'normal' breast biopsy specimens. Sections were stained immunohistochemically for TGF alpha. The staining was assessed semi-quantitatively taking into account both the staining intensity and the proportion of cells stained.. Minimal expression of TGF alpha was observed in normal breast tissue. Increased levels of expression were seen in ductal hyperplasia, atypical ductal hyperplasia, and ductal carcinoma in situ. Increased levels of expression of TGF alpha were also found in morphologically normal ducts immediately adjacent to areas of intraduct epithelial proliferation.. Increased expression of TGF alpha occurs in the early stages of intraduct epithelial proliferation and will not help the histopathologist distinguish atypical ductal hyperplasia from either ductal hyperplasia or ductal carcinoma in situ. The molecular changes within a cell may precede the morphological changes observed by light microscopy thereby reflecting the biological potential of the epithelium.

Topics: Adult; Aged; Breast; Breast Neoplasms; Carcinoma in Situ; Carcinoma, Intraductal, Noninfiltrating; Female; Humans; Hyperplasia; Middle Aged; Precancerous Conditions; Transforming Growth Factor alpha