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To K.,Experimental Medicine Program | To K.,Child and Family Research Institute | Fotovati A.,Child and Family Research Institute | Reipas K.M.,Experimental Medicine Program | And 19 more authors.
Cancer Research | Year: 2010

Y-box binding protein-1 (YB-1) is an oncogenic transcription/translation factor expressed in >40% of breast cancers, where it is associated with poor prognosis, disease recurrence, and drug resistance. We questioned whether this may be linked to the ability of YB-1 to induce the expression of genes linked to cancer stem cells such as CD44 and CD49f. Herein, we report that YB-1 binds the CD44 and CD49f promoters to transcriptionally upregulate their expressions. The introduction of wild-type (WT) YB-1 or activated P-YB-1S102 stimulated the production of CD44 and CD49f in MDA-MB-231 and SUM 149 breast cancer cell lines. YB-1-transfected cells also bound to the CD44 ligand hyaluronan more than the control cells. Similarly, YB-1 was induced in immortalized breast epithelial cells and upregulated CD44. Conversely, silencing YB-1 decreased CD44 expression as well as reporter activity in SUM 149 cells. In mice, expression of YB-1 in the mammary gland induces CD44 and CD49f with associated hyperplasia. Further, activated mutant YB-1S102D enhances self-renewal, primary and secondary mammosphere growth, and soft-agar colony growth,. which were reversible via loss of CD44 or CD49f. We next addressed the consequence of this system on therapeutic responsiveness. Here, we show that paclitaxel induces P-YB-1S102 expression, nuclear localization of activated YB-1, and CD44 expression. The overexpression of WT YB-1 promotes mammosphere growth in the presence of paclitaxel. Importantly, targeting YB-1 sensitized the CD44High/CD24Low cells to paclitaxel. In conclusion, YB-1 promotes cancer cell growth and drug resistance through its induction of CD44 and CD49f. © 2010 American Association for Cancer Research.


Dhillon J.,Experimental Medicine Program | Dhillon J.,University of British Columbia | Astanehe A.,Experimental Medicine Program | Astanehe A.,University of British Columbia | And 6 more authors.
Oncogene | Year: 2010

The development of acquired resistance to trastuzumab remains a prevalent challenge in the treatment of patients whose tumors express human epidermal growth factor 2 (HER2). We previously reported that HER2 overexpressing breast cancers are dependent on Y-box binding protein-1 (YB-1) for growth and survival. As YB-1 is also linked to drug resistance in other types of cancer, we address its possible role in trastuzumab insensitivity. Employing an in vivo model of acquired resistance, we demonstrate that resistant cell lines have elevated levels of P-YB-1 S102 and its activating kinase P-RSK and these levels are sustained following trastuzumab treatment. Further, to demonstrate the importance of YB-1 in mediating drug resistance, the expression of the active mutant YB-1 S102D rendered the BT474 cell line insensitive to trastuzumab. Questioning the role of tumor-initiating cells (TIC) and their ability to escape cancer therapies, we investigate YB-1's role in inducing the cancer stem cell marker CD44. Notably, the resistant cells express more CD44 mRNA and protein compared with BT474 cells, which correlated with increased mammosphere formation. Expression of YB-1 S102D in the BT474 cells increase CD44 protein levels, resulting in enhanced mammosphere formation. Further, exposing BT474 cells to trastuzumab selected for a resistant sub-population enriched for CD44. Conversely, small intefering RNA inhibition of CD44 restored trastuzumab sensitivity in the resistant cell lines. Our findings provide insight on a novel mechanism employed by tumor cells to acquire the ability to escape the effects of trastuzumab and suggest that targeting YB-1 may overcome resistance by eliminating the unresponsive TIC population, rendering the cancer sensitive to therapy. © 2010 Macmillan Publishers Limited All rights reserved.


PubMed | Experimental Medicine Program
Type: Journal Article | Journal: Oncogene | Year: 2010

The development of acquired resistance to trastuzumab remains a prevalent challenge in the treatment of patients whose tumors express human epidermal growth factor 2 (HER2). We previously reported that HER2 overexpressing breast cancers are dependent on Y-box binding protein-1 (YB-1) for growth and survival. As YB-1 is also linked to drug resistance in other types of cancer, we address its possible role in trastuzumab insensitivity. Employing an in vivo model of acquired resistance, we demonstrate that resistant cell lines have elevated levels of P-YB-1(S102) and its activating kinase P-RSK and these levels are sustained following trastuzumab treatment. Further, to demonstrate the importance of YB-1 in mediating drug resistance, the expression of the active mutant YB-1(S102D) rendered the BT474 cell line insensitive to trastuzumab. Questioning the role of tumor-initiating cells (TIC) and their ability to escape cancer therapies, we investigate YB-1s role in inducing the cancer stem cell marker CD44. Notably, the resistant cells express more CD44 mRNA and protein compared with BT474 cells, which correlated with increased mammosphere formation. Expression of YB-1(S102D) in the BT474 cells increase CD44 protein levels, resulting in enhanced mammosphere formation. Further, exposing BT474 cells to trastuzumab selected for a resistant sub-population enriched for CD44. Conversely, small intefering RNA inhibition of CD44 restored trastuzumab sensitivity in the resistant cell lines. Our findings provide insight on a novel mechanism employed by tumor cells to acquire the ability to escape the effects of trastuzumab and suggest that targeting YB-1 may overcome resistance by eliminating the unresponsive TIC population, rendering the cancer sensitive to therapy.


News Article | December 13, 2016
Site: www.sciencemag.org

In early 2013, scientists working in a laboratory led by a prominent cancer researcher at the University of British Columbia (UBC) in Vancouver, Canada, were getting worried. They were unable to reproduce results from several of the researcher’s experiments, and suspected some of the original work was fraudulent. An investigation by UBC ultimately confirmed their fears: In 2014, investigators identified 29 instances of scholarly misconduct, 16 of them “serious,” including falsification and fabrication of data, according to university correspondence obtained by Retraction Watch. The tainted work had been included in 12 papers published in six journals between 2005 and 2012, investigators found, and had drawn financial support from more than a dozen government and private funders. To the dismay of some scientists familiar with the case, however, UBC never publicly released the damning report or named the researcher, who has since left the institution. Canadian policy does not require the university or federal funding agencies to disclose the researcher’s name. And a spokesperson for the university says its hands are tied by British Columbia’s privacy laws, which prohibit it from disclosing personal information unless it is “clearly” in the public interest. But critics say the case highlights a troubling lack of transparency in Canada’s system for policing scientific misconduct. Some believe the secrecy allows unreliable papers to remain in circulation, and could enable researchers to continue to raise funds from donors and investors who may not be aware of misconduct findings. The university is “obviously trying to limit dissemination of information,” and that is a “huge mistake,” says UBC biochemist Ivan Sadowski, a member of a three-person team that made the misconduct findings. The researcher at the center of the case is Sandra Dunn, according to the UBC documents. (Repeated attempts to contact Dunn were unsuccessful.) For nearly 15 years, Dunn ran a lab at UBC’s Experimental Medicine Program, where she worked on new treatments for aggressive brain and breast cancers. Dunn, once featured as an expert on a panel organized by the Canadian Breast Cancer Foundation, secured at least CAD$1.1 million in government funding between 2009 and 2015. She left the university in 2015, after UBC concluded its investigation, to run Phoenix Molecular Designs, a company based in Richmond, Canada, that she founded in 2012. The company says it develops cancer therapies, and lists charities—including one supported by the parents of a child who died of cancer—among its “partners and supporters.” Many of Dunn’s past and current private funders may not be aware of UBC’s misconduct findings. The UBC correspondence lists 15 outside funders that directly or indirectly supported Dunn’s work, and recommended that UBC contact them “as necessary.” Retraction Watch tried to contact the funders; of the 10 that responded, only one—the C17 foundation in Edmonton, Canada—said it was aware of UBC’s investigation. Some said they would not expect to be informed, because they had not directly funded Dunn. And one current funder, the Michael Cuccione Foundation in Vancouver, said that UBC had not contacted it about the investigation, but that it was not concerned. The foundation has supported Dunn for years, says Executive Director Gloria Cuccione, and she has done “unbelievable work.” None of the 12 papers identified by investigators has been retracted, but Molecular Pharmacology recently published an “expression of concern” about one of the papers, citing UBC’s investigation. Breast Cancer Research, a journal that published two of the papers, confirmed that UBC had informed it of the findings. Although UBC has no legal obligation to publicly disclose details of its misconduct investigations, it is required to notify federal funding agencies of misconduct findings against researchers that the agencies have supported. The agencies then decide whether releasing the name is in the public interest. In 2011, agencies started requiring all funding applicants to consent to having their names publicized if they commit a serious breach of agency policy. Dunn’s funding predated the 2011 policy, however, and so far the policy has not led to the public naming of any offending scientists (although one agency recently named an offender under a different set of rules). Some Canadian researchers would like to see their funding agencies follow the lead of the U.S. Department of Health and Human Service’s Office of Research Integrity, which does name researchers it concludes have committed misconduct. (The U.S. National Science Foundation does not.) Current practices in Canada are “nothing but a cover-up with the excuse of privacy laid on top of it,” argues Amir Attaran, a law professor and biologist at the University of Ottawa. Research institutions face a tricky task in balancing the need for public transparency with the right to privacy, says Paul Hébert of the University of Montreal. Misconduct findings can be “extremely disruptive,” he says, and there’s a danger that colleagues of the offending researcher can be “painted with the same brush.” Still, Hébert would like to see Canada improve its misconduct monitoring system. As it stands, he says, there is too little transparency and “no policing. … Universities as research institutes investigate themselves.” This story is the product of a collaboration between Science and Retraction Watch.

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