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Background Differences in the breast cancer burden of African American compared with White American women are well-documented. Recent controversies have emerged regarding age-appropriate mammographic screening guidelines, and these surveillance recommendations may influence future breast cancer disparities. Our goal was to evaluate age-specific breast cancer stage distributions and incidence rates of triple-negative breast cancer (TNBC) in a population-based tumor registry. Study Design We analyzed California Cancer Registry (CCR) breast cancers diagnosed 1988 – 2006. Results were stratified by age and race/ethnicity, with White Americans identified as Non-Hispanic Whites (NHW) and African Americans as Non-Hispanic Blacks (NHB). Breast cancer stage distributions and TNBC incidence rates were also analyzed. Results A total of 375,761 invasive breast cancers were evaluated (including 276,938 in NHW and 21,681 in NHB) NHB and Hispanics tended to be younger than NHW (median ages 57; 54; and 64 years, respectively). Lifetime incidence rates were higher for NHW compared to NHB and Hispanics, but for women younger than 44 years incidence was highest among NHB. NHB also had higher incidence rates of Stage III and IV disease, and higher incidence of TNBC in all age categories. Conclusions Population-based data demonstrate that African American women have a more advanced stage distribution for breast cancer compared to White Americans, and higher incidence rates for TNBC. These patterns are observed for women age 40–49 years as well as older women, and suggest that mammographic screening for early detection of breast cancer will be particularly relevant for younger African American women.

The evolutionarily conserved DOCK180 protein has an indispensable role in cell migration by functioning as an exchange factor for Rac GTPase via its DOCK homology region (DHR)-2 domain. We report here that the conserved DHR-1 domain also has an important signalling role. A form of DOCK180 that lacks DHR-1 fails to promote cell migration, although it is capable of inducing Rac GTP-loading. The DHR-1 domain interacts with PtdIns(3,4,5)P(3) in vitro and in vivo, and mediates the DOCK180 signalling complex localization at sites of PtdIns(3,4,5)P(3) accumulation in the cell's leading edge. A form of DOCK180 in which the DHR-1 domain has been replaced by a canonical PtdIns(3,4,5)P(3)-binding pleckstrin homology domain is fully functional at inducing cell elongation and migration, suggesting that the main function of DHR-1 is to bind PtdIns(3,4,5)P(3). These results demonstrate that DOCK180, via its DHR-1 and DHR-2 domains, couples PtdIns(3,4,5)P(3) signalling to Rac GTP-loading, which is essential for directional cell movement.

The unc-52 gene encodes the nematode homologue of mammalian perlecan, the major heparan sulfate proteoglycan of the extracellular matrix. This is a large complex protein with regions similar to low-density lipoprotein receptors, laminin, and neural cell adhesion molecules (NCAMs). In this study, we extend our earlier work and demonstrate that a number of complex isoforms of this protein are expressed through alternative splicing. We identified three major classes of perlecan isoforms: a short form lacking the NCAM region and the C-terminal agrin-like region; a medium form containing the NCAM region, but still lacking the agrin-like region; and a newly identified long form that contains all five domains present in mammalian perlecan.Using region-specific antibodies and unc-52 mutants, we reveal a complex spatial and temporal expression pattern for these UNC-52 isoforms. As well, using a series of mutations affecting different regions and thus different isoforms of UNC-52, we demonstrate that the medium NCAM-containing isoforms are sufficient for myofilament lattice assembly in developing nematode body-wall muscle. Neither short isoforms nor isoforms containing the C-terminal agrin-like region are essential for sarcomere assembly or muscle cell attachment, and their role in development remains unclear. INTRODUCTIONBasement membranes are specialized regions of extracellular matrix (ECM) that have important roles in many fundamental developmental and regenerative processes, including cell adhesion and migration, signal transduction, and even gene regulation (Martin and Timpl, 1987;Yurchenco and Schittny, 1990). Many of these processes are mediated by specific interactions between basement membrane components and transmembrane receptors such as integrin (Hynes, 1992). Basement membranes contain a large number of different components, including laminin, collagen, nidogen, and heparan sulfate proteoglycans (Yurchenco and O'Rear, 1994;Timpl and Brown, 1996). Homologues of these proteins have been identified in the nematode Caenorhabditis elegans (reviewed in Kramer, 1997), and mutations are associated with several of these components (Guo et al., 1991;Ishii et al., 1992;Rogalski et al., 1993;Sibley et al., 1993). This genetic approach is helping to reveal the function of these basement membrane proteins during morphogenesis. In this study, we focus on perlecan, the major basement membrane heparan sulfate proteoglycan, and its role in muscle development in C. elegans.In C. elegans, a specialized basement membrane underlies the body-wall muscles and anchors the myofilament lattice through integrin-containing adhesion complexes (reviewed in Moerman and Fire, 1997). In adult animals, there are 95 body-wall muscle cells arranged in four quadrants, two dorsal and two ventral, beneath the hypodermis (reviewed in . Each quadrant runs the length of the animal and consists of a double row of spindle-shaped cells. Within each muscle cell, the thin and thick filaments of the myofilament lattice lie just beneath the plasma membrane ...

Extensive studies indicate that both p53 and multidrug transporters play important roles in chemoresistance. Since the initial reports a decade ago demonstrating a transcriptional dependence of the ABCB1 gene (MDR) promoter by p53, much data have been accumulated. However, despite being the subject of intense study, this p53-MDR relationship remains unclear in human cancers. The data are confounded by variable and contrasting results when considering the in vitro regulation and attempting to draw parallels in tissue specimens. The original model suggested that wild-type p53 downregulates the ABCB1 promoter, whereas mutant p53 increases expression of ABCB1. This review summarizes the data for and against this hypothesis. What emerges from these studies is a complex picture, where data have been obtained in support of this hypothesis, but there are also many circumstances where it is not supported. Taken together, these data suggest that the relationship between p53 and multidrug transporters is conditional. It is dependent on cellular environment, the drug used, and the nature of the p53 mutation.

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Cutaneous malignant melanoma is a life-threatening cancer with poor prognosis due to a high metastasis potential. The main obstacle in treatment of metastatic melanoma is the resistance to chemotherapy. Recent studies indicated that apoptosis is a common mechanism of action for various cytotoxic agents. As p53 plays an important part in apoptosis, we investigated the role of p53 in chemosensitivity of melanoma cells. Previously, we found that melanoma cell lines containing wild-type p53 have significantly higher response rates to chemotherapy than cell lines with a mutant p53 gene. To confirm the role of p53 in melanoma chemosensitivity further, we transfected an expression vector, pED1, which carries a mutant p53 gene, into a wild-type p53 melanoma cell line, MMAN. We examined the effect of mutant p53 on camptothecin-induced apoptosis and the expression of genes which are known to be involved in apoptosis or drug resistance, such as bcl-2, bax, bak, p21waf1, and P-glycoprotein. Our results indicate that overexpression of the mutant p53 increased the growth rate of MMAN cells, reduced the sensitivity to camptothecin, and lowered drug-induced apoptosis by 2-3-fold. Flow cytometry indicated that the camptothecin-induced apoptosis is not associated with G1 arrest. Furthermore, camptothecin treatment reduced bcl-2 and P-glycoprotein expression in wild-type p53 MMAN cells, but not cells overexpressing mutant p53. These results demonstrate that p53 mutational status is a determinant of melanoma chemosensitivity. p53 may downregulate bcl-2 and P-glycoprotein to induce apoptosis in melanoma cells after chemotherapy.

BackgroundQuercetin (QCT), a naturally occurring flavonoid has a wide array of pharmacological properties such as anticancer, antioxidant and anti-inflammatory activities. QCT has low solubility in water and poor bioavailability, which limited its use as a therapeutic molecule. Polymeric micelles (PMs) is a novel drug delivery system having characteristics like smaller particle size, higher drug loading, sustained drug release, high stability, increased cellular uptake and improved therapeutic potential. In the present study, we have formulated and characterized mixed PMs (MPMs) containing QCT for increasing its anticancer potential.MethodsThe MPMs were prepared by thin film hydration method, and their physicochemical properties were characterized. The in vitro anticancer activity of the MPMs were tested in breast (MCF-7 and MDA-MB-231, epithelial and metastatic cancer cell lines, respectively), and ovarian (SKOV-3 and NCI/ADR, epithelial and multi-drug resistant cell lines, respectively) cancer.ResultsThe optimal MPM formulations were obtained from Pluronic polymers, P123 and P407 with molar ratio of 7:3 (A16); and P123, P407 and TPGS in the molar ratio of 7:2:1 (A22). The size of the particles before lyophilization (24.83±0.44 nm) and after lyophilisation (37.10±4.23 nm), drug loading (8.75±0.41%), and encapsulation efficiency (87.48±4.15%) for formulation A16 were determined. For formulation A22, the particle size before lyophilization, after lyophilization, drug loading and encapsulation efficiency were 26.37±2.19 nm, 45.88±13.80 nm, 9.01±0.11% and 90.07±1.09%, respectively. The MPMs exhibited sustained release of QCT compared to free QCT as demonstrated from in vitro release experiments. The solubility of QCT was markedly improved compared to pure QCT. The MPMs were highly stable in aqueous media as demonstrated by their low critical micelle concentration. The concentration which inhibited 50% growth (IC50) values of both micellar preparations in all the cancer cell lines were significantly less compared to free QCT.ConclusionBoth the MPMs containing QCT could be used for effective delivery to different type of cancer and may be considered for further development.