Breaking a Feedback Loop May Trigger Cell Death in Triple Negative Breast Cancer Interview with:

James R. Lambert, PhD. Department of Pathology University of Colorado Anschutz Medical Campus Aurora, CO

Dr. Jim Lambert

James R. Lambert, PhD.
Department of Pathology
University of Colorado Anschutz Medical Campus
Aurora, CO What is the background for this study? What are the main findings?

Response: Our laboratory has been investigating a novel small molecule drug, AMPI-109, as a targeted therapeutic agent for triple-negative breast cancer (TNBC). We demonstrated that AMPI-109 is a potent inducer of apoptosis in TNBC cells and that its cell killing activities are largely specific for the TNBC subtype of breast cancer. Through our efforts to identify the molecular mechanism of AMPI-109 action in TNBC cells we identified the oncogenic phosphatase, PRL-3 as a mediator of AMPI-109 action and as a potential direct target of the drug in TNBC cells.

Our studies have defined PRL-3 as an oncogenic driver of  triple-negative breast cancer as exemplified by knocking down PRL-3 using shRNAs, or treating TNBC cells with AMPI-109, ultimately results in TNBC cell apoptosis. We thus became interested in elucidating the mechanisms whereby loss of PRL-3 expression, or function, results in cell death. During the course of these investigations we noted that at early times following PRL-3 knock down TNBC cells undergo a period of cell senescence followed by induction of apoptosis. This dynamic reprogramming of  triple-negative breast cancer cell fate was determined to be mediated through signaling events mediated by an autocrine tumor necrosis factor receptor 1 (TNF-R1) feedback loop. TNF-R1, which binds the pro-inflammatory cytokine TNFα, is a widely studied mediator of both cell survival and cell death yet the precise molecular mechanism controlling this toggling effect of TNF-R1 on TNBC cells remained largely unknown.

In this report, we demonstrate that PRL-3 is transcriptionally regulated by the pro-inflammatory NF-ĸB pathway in  triple-negative breast cancer cells, and that PRL-3 knock down elicits an autocrine TNF-R1 feedback loop that results in cell cycle arrest and senescence as a pre-determinant to engaging apoptosis of TNBC cells. These studies reveal a previously undescribed mechanism for how PRL-3 influences TNBC cell growth and further increase our understanding of the role of TNFα signaling in the disease. What should readers take away from your report?

Response: Our data reveal a heretofore undescribed role for PRL-3 in TNBC biology. By engaging the adaptive signaling programs of the TNF-R1 pathway, loss of PRL-3 expression induces cellular senescence and upregulates TNFα to convert senescent  triple-negative breast cancer tumor cells into apoptotic cells. This is a notably dynamic cellular response to reduced expression of an oncogenic phosphatase, particularly in the diverse background of genomic and proteomic alterations that are often associated with TNBC. Because high levels of PRL-3 expression are frequently observed in a variety of cancer types, our studies further demonstrate the potential utility of therapeutically targeting the PRL-3 signaling axis. Additionally, our studies propose that by inhibiting PRL-3 activity, such as with AMPI-109, PRL-3 blockade may serve as one mechanism to signal or “flag” to the immune system where the tumor is, and in essence could sensitize tumors to immunotherapy. The result is a two-hit strategy to expose the tumor and then allow the immune system to recognize and combat it. What recommendations do you have for future research as a result of this study?

Response: Our studies suggest that further investigations into the oncogenic role of PRL-3 in TNBC are warranted. Little is currently known regarding substrates for PRL-3 in the context of TNBC. The identification of PRL-3 substrates and signaling pathways will enhance our understanding of the role of PRL-3 in TNBC and perhaps, other cancers. Furthermore, our identification of PRL-3 as a potential target of AMPI-109 in TNBC suggest that PRL-3 may serve as a predictive biomarker for response of TNBC tumors to AMPI-109. Experiments addressing this issue are currently being performed in our laboratory and should provide essential insight into the use of AMPI-109 to impact the PRL-3 signaling axis in TNBC. Ultimately, it is anticipated that these studies will provide increased understanding of the molecular underpinnings of this aggressive disease and demonstrate proof-of-concept that AMPI-109 can be used as a tool to identify unique oncogenic drivers of TNBC. Thank you for your contribution to the community.


 H H Gari, G D DeGala, M S Lucia, J R Lambert. Loss of the oncogenic phosphatase PRL-3 promotes a TNF-R1 feedback loop that mediates triple-negative breast cancer growth. Oncogenesis, 2016; 5 (8): e255 DOI: 10.1038/oncsis.2016.50

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

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