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Localization of transforming growth factor-beta isotypes in lesions of the human breast
B K McCune1, B R Mullin, K C Flanders
1Laboratory of Chemoprevention, National Cancer Institute, Bethesda, MD.
Abstract:
Transforming growth factor-beta s (TGF-beta) comprise a highly conserved family of multifunctional cell regulatory peptides that may play a role in a variety of pathologic processes. To date, five TGF-beta isotypes have been identified, three of these in mammalian systems. A number of cultured human breast carcinoma cell lines produce biologically inactive latent TGF-beta and are growth inhibited by activated TGF-beta; TGF-beta production is estrogen-influenced in some of these cell lines. To investigate the potential role of the TGF-beta isotypes in human breast disease, we localized TGF-beta s 1, 2, and 3 immunohistochemically in normal breast, fibrocystic change, epithelial hyperplasia, sclerosing adenosis, fibroadenoma, cystosarcoma phyllodes, and several carcinoma variants. Transforming growth factor-beta s 1, 2, and 3 were identified intracellularly in most active mammary epithelia, regardless of the lesion, including carcinoma; the associated stroma contained little or no intracellular TGF-beta. An antibody that recognizes an extracellular conformation of TGF-beta stained normal intralobular stroma and, more extensively, the stroma of active fibroadenomas and low-grade phyllodes tumors and the desmoplastic stroma of carcinomas. The results indicate the potential for paracrine and autocrine regulation of the mammary gland by TGF-beta and suggest an association between TGF-beta and abnormal stromal proliferations. Altered expression of TGF-beta s 1, 2, and 3 at the protein level in mammary epithelia appears not to be a major feature of most breast lesions, raising the possibility that altered cellular response to the TGF-beta already present may play a role in the development of breast disease.
Insights
Transforming growth factor-beta (TGF-beta) isotypes 1, 2, and 3 are found in mammary epithelia across various breast lesions. Their presence in stroma suggests paracrine regulation and a link to abnormal stromal growth in breast disease.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- Transforming growth factor-beta (TGF-beta) is a family of multifunctional peptides involved in various pathological processes.
- Five TGF-beta isotypes exist, with three identified in mammals.
- Some human breast carcinoma cell lines produce inactive TGF-beta and are inhibited by activated TGF-beta, with estrogen influencing production.
Purpose of the Study:
- To investigate the role of TGF-beta isotypes 1, 2, and 3 in human breast disease.
- To localize these TGF-beta isotypes in normal breast tissue and various benign and malignant breast lesions using immunohistochemistry.
Main Methods:
- Immunohistochemical localization of TGF-beta 1, 2, and 3 in normal breast tissue and a spectrum of breast lesions.
- Utilized an antibody recognizing extracellular TGF-beta conformation to assess stromal staining.
Main Results:
- TGF-beta 1, 2, and 3 were detected intracellularly in most active mammary epithelia, including carcinomas.
- Intracellular TGF-beta was minimal in the associated stroma.
- Extracellular TGF-beta staining was observed in normal stroma, fibroadenomas, phyllodes tumors, and the desmoplastic stroma of carcinomas.
Conclusions:
- Results suggest potential for both paracrine and autocrine regulation of the mammary gland by TGF-beta.
- An association between TGF-beta and abnormal stromal proliferations in breast tissue is indicated.
- Altered cellular response to existing TGF-beta, rather than altered protein expression, may be crucial in breast disease development.