Epidermolytic palmoplantar keratosis (EPPK) cosegregates with breast and ovarian cancers in a large French pedigree, raising the possibility that a single genetic mutation might cause these conditions and offering a potential lead to the identification of a hereditary breast/ovarian cancer gene. We have performed linkage analysis and show that the EPPK locus lies on the long arm of chromosome 17 near the type I keratin gene cluster and the proposed breast cancer gene (BRCA1). The type I keratin 9 gene has been partially sequenced in four affected individuals. A single base mutation within the rod domain of the protein cosegregates with EPPK in all affected individuals tested. Although inheritance of this mutation is likely responsible for EPPK, it is unlikely to be the cause of the breast and ovarian cancer.

Binding and uptake of a-fetoprotein (AFP) by mouse T-lymphoma YAC-1 cells exhibited the characteristics of receptor-mediated endocytosis. The (2,3). On the other hand, AFP can be localized during ontogenic development in practically all tissue derived from the three embryonic germ layers (4). The intracellular presence of AFP in fetal tissues other than the liver and the yolk sac is due to active uptake of the protein (5, 6) and not local synthesis (3, 7). It has also been shown that the ability to internalize AFP may be shared by neoplastic cells of different origin, such as spontaneous mammary carcinomas growing in the mouse (8), as well as in two cultured cell lines derived from a rat rhabdomyosarcoma (9) and a human breast carcinoma (10). Preliminary morphological observations of AFP uptake by these cultured cells suggested the existence of a receptor-mediated mechanism. To confirm this and to assess whether AFP receptors in malignant cells are or are not shared by normal cell counterparts, we used as experimental models a lymphoid tumor cell line, YAC-1, and normal adult T lymphocytes. The YAC-1 cell line, derived from a Moloney murine leukemia virus-induced lymphoma, has several features that make it useful for receptor and uptake studies. It is a stable cell line with morphological characteristics of poorly differentiated cells that grow in suspension. The latter is advantageous for proteinuptake experiments using radiolabeled protein derivatives.In the present work, we show that YAC-1 cells take up AFP through receptor-mediated endocytosis. Normal adult T lymphocytes, on the contrary, do not incorporate AFP. Other serum proteins tested, such as transferrin and a2-macroglobulin (a2M), are indiscriminately taken up by YAC-1 cells and normal T lymphocytes. MATERIALS AND METHODSCells. YAC-1 cells were cultured in RPMI-1640 medium supplemented with antibiotics and 10% fetal bovine serum, and they were maintained at 37°C in a humidified atmosphere with 5% C02/95% air. Cells were seeded at densities of 5-10 x 104 cells per ml, and all experiments were done with cells harvested at a density of 5 x 105 cells per ml. Fetal calf serum contains 2-5 mg of AFP per ml. To avoid competitive effects between mouse and bovine AFP, prior to all experiments, cells were washed three or four times with RPMI-1640 medium. This was followed by a 60-min incubation at 37°C in the same medium, which removed most of internalized bovine AFP (see Fig. 5). After this treatment, immunocytochemical staining of cells with antibodies to bovine AFP was negative. The cells were then suspended (1.5-2 x 107 cells per ml) in RPMI-1640 medium at 4°C. In experiments carried out at 4°C, the pH of the medium was adjusted to 7.4 with a minimal amount of potassium phosphate. Suspensions of thymocytes were obtained from fetal (18-20 days of gestation), newborn, and 5-week-old Swiss mice. Thymuses were minced and passed through a 200-mm mesh stainless steel sieve, and the cells were subsequently washed with RPMI-1640 medium. The T lymphocy...

No abstract

Failure of chemotherapy to control SCLC seems to be related to an acquired multidrug resistance involving the MDR1-mediated mechanism. Therapeutic benefit could therefore be expected from chemotherapy combined with inhibitors of MDR1.

No abstract