PubMed · 7842559
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W H Hindle. 1994. Other benign breast problems.. https://doi.org/10.1097/00003081-199412000-00018
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Multifunctional cytokines play important and only partially defined roles in mammary tumor development and progression. Normal human mammary epithelia] cells (MECs) constitutively produce interleukin (IL) 6, IL8, and a nonsecreted form of tumor necrosis factor. MEC transformation by different oncogenes is frequently associated with alterations of cytokine/growth factor production and responsiveness. This seems particularly true in the case of IL6. Histochemical studies showed that expression of immunoreactive IL6, as compared to normal tissue and to in situ lesions, is significantly reduced in invasive ductal carcinoma. Conversely, the expression of IL6 in invasive lobular carcinoma was enhanced. Expression of TGF-beta1 in mammary neoplasia was in general less intense than that seen in the normal mammary gland. In vitro studies partially supported the in vivo findings: expression of IL6 and TGF-beta1 was significantly down-regulated in cultures derived from both ductal carcinoma and peritumoral tissue. Similarly, responsiveness to IL6 and TGF-beta1 was significantly reduced in neoplastic MECs. The data suggest that alterations of cytokine pathways are present not only in mammary neoplasia, but also in pathologically unaffected breast tissues.
Mutations of the p53 gene are the most frequent genetic lesions in breast cancer, suggesting a critical role for p53 protein in normal mammary cell growth control. Indeed, the p53-targeting human papillomavirus oncogene E6 induces efficient immortalization of normal human mammary epithelial cells (MECs). To assess whether selective loss of p53 is sufficient for MEC immortalization, we introduced seven missense mutants and one single-amino acid deletion mutant (del239) of p53 into the 76N normal MEC strain. Although the missense mutants failed to immortalize MECs, the del239 mutant reproducibly immortalized these cells. The immortal cells were anchorage dependent and nontumorigenic, indicating a preneoplastic transformation. Gamma-irradiation of these cells failed to induce G1 cell cycle arrest and did not lead to an increase in WAF1 and mdm-2 mRNA levels, demonstrating a loss of the endogenous p53 function. These results demonstrate that selective ablation of p53 function by a dominant-negative mutant is sufficient for immortalization of MECs. Availability of an immortalizing as well as several nonimmortalizing p53 mutants should help identify functions critical for cell growth control by p53 in mammary epithelial cells.
The cyclin-dependent kinase 7 (CDK7) represents the 40-kDa catalytic subunit of the CDK-activating kinase, the enzyme responsible for activatory phosphorylation of multiple CDKs controlling G1, S and G2/M phases of the cell cycle. Here, we surveyed a wide range of normal and tumour cell types, in both cell culture and biopsy specimens, for abundance and subcellular localisation of the CDK7 protein. Immunoblotting and immunocytochemical analyses showed that CDK7 was (i) ubiquitously expressed in all cell types examined; (ii) exclusively nuclear; (iii) moderately elevated in tumour cells when compared with their normal cell counterparts; (iv) invariant throughout the cell cycle of normal lymphocytes, fibroblasts, breast epithelium and several cancer cell lines; and (v) clearly detectable even in quiescent cells, including highly differentiated cell types in situ. Our data are consistent with the emerging role for CDK7/CAK in multiple biological processes, possibly providing a link between cell-cycle control, transcriptional regulation and genomic integrity control.