Overexpression of the BCAR1 gene confers antiestrogen resistance on human ZR-75-1 breast cancer cells. Overexpression of BCAR1 in retrovirus-mutated cells appears to result from activation of the gene's promoter. The isolation and characterization of this gene open new avenues to elucidating mechanisms by which the growth of human breast cancer becomes independent of estrogen.

IGF‐I and IGF‐II are growth‐stimulating peptides with strong mitogenic properties. These polypeptide growth factors circulate in serum bound to specific binding proteins. We report the cloning and complete sequence of a cDNA encoding a low mol. wt IGF‐binding protein from a human placenta cDNA library. We propose the designation IGF‐binding protein 1 (IBP‐1) for the gene and corresponding protein. Expression of the cDNA encoding IBP‐1 in COS cells resulted in the synthesis of a 30‐kd protein which binds IGF‐I and is immunologically indistinguishable from the IGF‐binding protein isolated from amniotic fluid or human serum. Northern blotting analysis demonstrated that expression of the IBP‐1 gene is highly tissue specific and limited to placental membranes and fetal liver suggesting a rigid control. The IBP‐1 gene is a single copy gene, located on chromosome 7. The results obtained suggest that most, if not all, lower mol. wt IGF‐binding proteins originate from this gene.

The gene product of bacteriophage Mu gin catalyzes a 3,000-base-pair inversion in the DNA of the phage, thus changing its host range. In some strains of Escherichia coli there is a function that can complement Mu gin mutations. This function (pin) was cloned and shown to catalyze an inversion of 1,800 base pairs in the adjacent E coli DNA (P region). pin-derivatives carry the P. region frozen in the (+) or (-) orientation. The function of the switch is not yet clear. The sequences of gin and-pin were determined; they exhibit 70%.homology. The sequences around the recombination sites of Gin and Pin are also largely homologous; a consensus sequence is derived for the recombination sites of Gin and Pin, and of Hin in SalmoneUa typhimurium. The amino acid sequences of Gin, Pin, Hin, and TnpR are compared, and the evolutionary relationship between these prokaryotic site-specific recombination systems is discussed.Inversions of DNA segments in prokaryotes have been found -to serve different functions such as change of the host range of bacteriophage Mu (1-3) and-change of the flagellar antigen of Salmonella typhimurium (4). The NH2-terminal part of the Mu tail fiber gene is located in the noninverting DNA, and two different COOH-terminal parts of the gene are spliced to the constant part by inversion of the G region (2). In S. typhimurium, a promoter located in the invertible DNA can turnmon genes in the adjacent DNA (4). Although function and genetic organization of invertible DNA are different in these cases, all genes catalyzing inversions in prokaryotes have been shown to complement each other [gin of Mu, hin of S. typhimurium, and cin of phage P1 which is closely related to Mu (5-7)].We recently found a-function in the chromosome of Escherichia coli (pin) that complements Mu gin mutations and catalyzes the inversion of a 1,800-base-pair (bp) region of DNA (unpublished data). This function is found in E. coli strains HB101 and CSH520. To investigate this gene further, we cloned it and showed that Pin is responsible for the inversion of a region which we named P region. To compare the different DNA-invertase genes we determined the sequences of pin and gin. The comparison defines regions in the genes which are conserved in the invertases Gin, Pin, and Hin.It was previously noted that the proteins Hin and TnpR are

Tamoxifen has been used for the systemic treatment of patients with breast cancer for nearly three decades. Treatment success is primarily dependent on the presence of the estrogen receptor (ER) in the breast carcinoma. While about half of patients with advanced ER-positive disease immediately fail to respond to tamoxifen, in the responding patients the disease ultimately progresses to a resistant phenotype. The possible causes for intrinsic and acquired resistance have been attributed to the pharmacology of tamoxifen, alterations in the structure and function of the ER, the interactions with the tumour environment and genetic alterations in the tumour cells. So far no prominent mechanism leading to resistance has been identified. The recent results of a functional screen for breast cancer antiestrogen resis- tance (BCAR) genes responsible for development of tamoxifen resistance in human breast cancer cells are reviewed. Individual BCAR genes can transform estrogen-dependent breast cancer cells into estrogen-independent and tamoxifen-resistant cells in vitro. Furthermore, high levels of BCAR1/pl30Cas protein in ER-positive primary breast tumours are associated with intrinsic resistance to tamoxifen treatment. These results indicate a prominent role for alternative growth control pathways independent of ER signalling in intrinsic tamoxifen resistance of ER-positive breast carcinomas. Deciphering the differentiation characteristics of normal and malignant breast epithelial cells with respect to proliferation control and regulation of cell death (apoptosis) is essential for understanding therapy response and development of resistance of breast carcinoma.

Purpose: BCAR1, the human homologue of the rat p130Cas protein, was identified in a functional screen for human breast cancer cell proliferation resistant to antiestrogen drugs. Here, we study the prognostic value of quantitative BCAR1 levels in a large series of breast cancer specimens.Experimental Design: A specific ELISA was developed to measure BCAR1 protein levels in 2593 primary breast tumor cytosols. Tumor levels of BCAR1 were correlated with relapse-free survival (RFS) and overall survival (OS) and compared with collected data on urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor 1 (PAI-1).Results: In tumor cytosols, BCAR1 protein levels varied between 0.02 and 23 ng/mg protein. BCAR1 levels exhibited a positive correlation with steroid hormone receptor levels, age and menopausal status, and uPA and PAI-1 levels. The level of BCAR1 (continuous or categorized as low, intermediate, or high) was inversely related with RFS and OS time. Multivariate analysis showed that BCAR1 levels contributed independently to a base model containing the traditional prognostic factors for both RFS and OS (both P < 0.0001).When added together with uPA and PAI-1 in the multivariate model, BCAR1 contributed independently of PAI-1 and was favored over uPA. Interaction tests allowed for additional analyses of BCAR1 protein levels in clinically relevant subgroups stratified by nodal and menopausal status.Conclusions: The quantitative BCAR1 protein level represents a prognostic factor for RFS and OS in primary breast cancer, independent of the traditional prognostic factors and the other novel marker PAI-1.