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Gonzalez-Nieves R.,Uniformed Services University of the Health Sciences | Desantis A.I.,Uniformed Services University of the Health Sciences | Cutler M.L.,Uniformed Services University of the Health Sciences | Cutler M.L.,Murtha Cancer Center
Journal of Cell Communication and Signaling | Year: 2013

Cell adhesion and migration are complex processes that require integrin activation, the formation and dissolution of focal adhesion (FAs), and linkage of actin cytoskeleton to the FAs. The IPP (ILK, PINCH, Parvin) complex regulates FA formation via binding of the adaptor protein ILK to β1 integrin, PINCH and parvin. The signaling protein Rsu1 is linked to the complex via binding PINCH1. The role of Rsu1 and PINCH1 in adhesion and migration was examined in non-transformed mammary epithelial cells. Confocal microscopy revealed that the depletion of either Rsu1 or PINCH1 by siRNA in MCF10A cells decreased the number of focal adhesions and altered the distribution and localization of β1 integrin, vinculin, talin and paxillin without affecting the levels of FA protein expression. This correlated with reduced adhesion, failure to spread or migrate in response to EGF and a loss of actin stress fibers and caveolae. In addition, constitutive phosphorylation of actin regulatory proteins occurred in the absence of PINCH1. The depletion of Rsu1 caused significant reduction in PINCH1 implying that Rsu1 may function by regulating levels of PINCH1. However, while both Rsu1- or PINCH1-depleted cells retained the ability to activate adhesion signaling in response to EGF stimulation, only Rsu1 was required for EGF-induced p38 Map Kinase phosphorylation and ATF2 activation, suggesting an Rsu1 function independent from the IPP complex. Reconstitution of Rsu1-depleted cells with an Rsu1 mutant that does not bind to PINCH1 failed to restore FAs or migration but did promote spreading and constitutive p38 activation. These data show that Rsu1-PINCH1 association with ILK and the IPP complex is required for regulation of adhesion and migration but that Rsu1 has a critical role in linking integrin-induced adhesion to activation of p38 Map kinase signaling and cell spreading. Moreover, it suggests that Rsu1 may regulate p38 signaling from the IPP complex affecting other functions including survival. © 2013 The International CCN Society.


Kim Y.-C.,Uniformed Services University of the Health Sciences | Gonzalez-Nieves R.,Uniformed Services University of the Health Sciences | Gonzalez-Nieves R.,National Science Foundation | Cutler M.L.,Uniformed Services University of the Health Sciences | Cutler M.L.,Murtha Cancer Center
Cell Adhesion and Migration | Year: 2015

The ILK, PINCH, Parvin (IPP) complex regulates adhesion and migration via binding of ILK to β1 integrin and α-parvin thus linking focal adhesions to actin cytoskeleton. ILK also binds the adaptor protein PINCH which connects signaling proteins including Rsu1 to the complex. A recent study of Rsu1 and PINCH1 in non-transformed MCF10A human mammary epithelial cells revealed that the siRNA-mediated depletion of either Rsu1 or PINCH1 decreased the number of focal adhesions (FAs) and altered the distribution and localization of FA proteins. This correlated with reduced adhesion, failure to spread or migrate in response to EGF and a loss of actin stress fibers and caveolae. The depletion of Rsu1 caused significant reduction in PINCH1 implying that Rsu1 may function in part by regulating levels of PINCH1. However, Rsu1, but not PINCH1, was required for EGFinduced activation of p38 Map kinase and ATF2 phosphorylation, suggesting a Rsu1 function independent from the IPP complex. Reconstitution of Rsu1-depleted cells with a Rsu1 mutant (N92D) that does not bind to PINCH1 failed to restore FAs or migration but did promote IPP-independent spreading and constitutive as well as EGF-induced p38 activation. In this commentary we discuss p38 activity in adhesion and how Rsu1 expression may be linked to Map kinase kinase (MKK) activation and detachment-induced stress kinase signaling.


Ellsworth R.E.,Murtha Cancer Center | Mamula K.A.,Windber Research Institute | Costantino N.S.,Windber Research Institute | Deyarmin B.,Windber Research Institute | And 4 more authors.
Environmental Research | Year: 2015

Many environmental chemicals accumulate in human tissues and may contribute to cancer risk. Polychlorinated biphenyls (PCBs) are associated with adverse health effects, but relationships between PCB exposure and breast cancer are unclear. In this study, we sought to determine whether bioaccumulation of PCBs differs within regions of the human breast and whether PCB levels are associated with clinical and pathological characteristics in breast cancer patients. Tissue sections (. n=245) were collected from breast quadrants from 51 women with a diagnosis ranging from disease-free to metastatic breast cancer. Ninety-seven PCB congeners were assayed by high resolution gas chromatography. ANOVA was used to examine PCB distribution within the breast and relationships with clinical/pathological variables. Pearson product-moment correlations assessed relationships between age at mastectomy and PCB levels. PCBs were abundant in breast tissues with a median concentration of 293.4. ng/g lipid (range 15.4-1636.3. ng/g). PCB levels in breast tissue were significantly different (. p<0.001) among functional groupings of congeners defined by structure-activity properties: Group I (28.2. ng/g), Group II (96.6. ng/g), Group III (166.0. ng/g). Total PCB concentration was highly correlated with age at mastectomy, but the distribution of PCBs did not differ by breast quadrant. PCB levels were not associated with patient status or tumor characteristics. In conclusion, PCB congeners with carcinogenic potential were present at high levels in the human breast, but were not associated with clinical or pathological characteristics in breast cancer patients. © 2015 Elsevier Inc.


Blackburn H.L.,Windber Research Institute | Ellsworth D.L.,Windber Research Institute | Shriver C.D.,U.S. National Institutes of Health | Ellsworth R.E.,Murtha Cancer Center
Cancer Causes and Control | Year: 2015

Purpose: The cytochrome P450 (CYP) genes are oxygenases involved in estrogen biosynthesis and metabolism, generation of DNA damaging procarcinogens, and response to anti-estrogen therapies. Since lifetime estrogen exposure is an established risk factor for breast cancer, determining the role of CYP genes in breast cancer etiology may provide critical information for understanding tumorigenesis and response to treatment.Methods: This review summarizes literature available in PubMed published between 1993 and 2013 that focuses on studies evaluating the effects of DNA variants in CYP genes on estrogen synthesis, metabolism, and generation of procarcinogens in addition to response to anti-estrogen therapies.Results: Evaluation of DNA variants in estrogen metabolism genes was largely inconclusive. Meta-analyses of data from CYP19A1 support an association between the number of (TTTA)n repeats in intron 4 and breast cancer risk, but the biological mechanism for this relationship is unknown. Associations between single nucleotide polymorphism in CYP1B1 and DNA damage caused by procarcinogenic estrogen metabolites were ambiguous. Variants in CYP2D6 are associated with altered metabolism tamoxifen; however, current data do not support widespread clinical testing. The effect of variants in CYP19A1 in response to aromatase inhibitors is also questionable.Conclusion: Evaluation of DNA variants in CYP genes involved with estrogen metabolism or treatment response has been inconclusive, reflecting small samples sizes, tumor heterogeneity, and differences between populations. Better-powered studies that account for genetic backgrounds and tumor phenotypes are thus necessary. © 2014, Springer International Publishing Switzerland.


News Article | January 13, 2016
Site: www.fastcompany.com

It wasn't expected to be a major State of the Union address—a final speech from a president in his last term, recounting achievements and expressing hope for the future. And then Obama made some news: "Let’s make America the country that cures cancer once and for all." And to lead the administration's effort, the president picked VP Joe Biden, who recently lost his son Beau to cancer, and who has said that finding a cure is one of his major life goals. Obama compared the effort to a moonshot, and he's not the only one to do this. His State of the Union address came just one day after the launch of another effort, led by big pharma and biotech companies, dubbed Cancer MoonShot 2020. The leader of MoonShot 2020, biotech company NantWorks' controversial founder and CEO Dr. Patrick Soon-Shiong, is one of the people who has met with the vice president to discuss radical cancer-treating approaches and has influenced Biden's thinking on the topic, reports the New York Times. At least one branch of the federal government, the John P. Murtha Cancer Center at Walter Reed Military Hospital, is on record as supporting Soon-Shiong's MoonShot. With details still to come about the administration's moonshot, Soon-Shiong's project offers a few hints of what these new cancer-fighting approaches may entail. His project, formally announced on January 11, is a switch from chemotherapy to immunotherapy; from killing cancer cells directly to helping the body's immune system kill cancer. It is focused on personalized genetic sequencing to develop custom treatments for each patient. And the time frame is at least as aggressive as the race to the moon. Within five years, it aims to not only design but also implement clinical trials of new immunotherapies for 20 tumor types in up to 20,000 patients. By 2020, these trials are expected to get as far as phase 3—widespread participation on an unheard-of timeframe. Though it's a nonprofit, MoonShot 2020 is led by big pharma firms like Celgene and Amgen, and biotech companies including NantKwest, Etubics, Altor Bioscience, and Precision Biologics. Participating hospitals and universities include Massachusetts General Hospital, Johns Hopkins University, the University of Miami, the University of Utah, and the Tufts Cancer Center. One biotech company, NantWorks, is spearheading the effort and is the key link to Biden, who reached out to Soon-Shiong as Beau Biden was still battling the disease. According to the Times, the VP became a believer in Soon-Shiong's radical approach to cancer, which the physician was already calling a moonshot in a two-page proposal he gave to the VP. In announcing that he would not run for president, Biden expressed his support for Soon-Shiong's vision, saying, " I believe that we need a moonshot in this country to cure cancer. It's personal. But I know we can do this." Biden later added, "If I could be anything, I would have wanted to have been the president that ended cancer, because it's possible." Instead, he aspires to be the VP who does. The exact nature of the Obama's administration's support for the moonshot immunotherapy approach remains unclear. Any tests will have to follow federal guidelines, of course, and government can play a role in speeding up approvals. The biggest commitment so far is from the US military through the participation of the John P. Murtha Cancer Center at Walter Reed Military Hospital, in part by sourcing participants. "We validate big science through our clinical trials network," wrote Col. Craig Shriver, M.D., of the Murtha Center in the MoonShot program's press release. "There are 1.2 million active duty military members, 9.3 million beneficiaries that receive military health care. That’s a huge network." Note: An earlier version of this article incorrectly characterized Obama's comments as a formal endorsement of Dr. Soon-Shiong's MoonShot program.

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