Poster Presentation 32nd Lorne Cancer 2020

cMyc as the master regulator of dormancy in triple negative breast cancer (#340)

Charlotte C Roelofs 1 2 , Annanya Chakrabati A Chakrabati 3 , Rick R Redvers 1 2 , Robin R Anderson 1 2 3
  1. School of Cancer Biology, La Trobe University, Melbourne, Victoria, Australia
  2. Olivia Newton-John Cancer Research Institute, Melbourne, VICTORIA, Australia
  3. Department of Oncology, Sir Peter MacCallum Department of Oncology, Melbourne, Victoria, Australia

18,200 Australians will be diagnosed with breast cancer in 2019. As many as one third of breast cancer patients will have disseminated tumour cells at the time of diagnosis, due to early spread away from the primary site. For patients not diagnosed with detectable metastatic disease, the five-year survival rate is greater than 90%. Nevertheless, some patients will relapse sometimes even decades following the initial diagnosis. This suggests the presence of a population of dormant tumour cells. The patient relapses when these cells start proliferating again and form macrometastases in distant organs. As of yet, it is unknown what drives the switch from the dormant to the proliferating phenotype.

cMyc is a potent oncogene which is involved in tumourigenesis of many cancers, such as breast cancer. The gene is aberrantly expressed in over 70% of all cancers. Furthermore, cMyc plays a role in stemness, pluripotency and proliferation, making it a potential regulator of dormancy in cancer. We hypothesise that an increase in cMyc expression in dormant breast cancer cells leads to rapid proliferation, break of dormancy and potential relapse. Conversely, we hypothesise that knockdown of the protein may induce dormancy and prevent metastasis.

In order to examine the role of cMyc in dormancy, a panel of direct and indirect cMyc inhibitors will be tested in vitro on mouse and human cell lines with highly metastatic phenotypes. To complement this, highly metastatic breast cancer cell lines with an inducible cMyc shRNA will be generated. Conversely, mouse and human cell lines with a dormant phenotype will be transduced with a cMyc-overexpressing vector. The inhibitors and the inducible cell lines will be used in an in vitro dormancy assay, which will resolve whether cMyc levels influence the escape of dormancy. Though cMyc represents a challenging therapeutic target in the clinical setting, identification of its overexpression in tumour biopsies may provide information on the risk of relapse, and thus would enable more effective monitoring.

  1. Reddy SM, Barcenas CH, Sinha AK, Hsu L, Moulder SL, Tripathy D, et al. Long-term survival outcomes of triple-receptor negative breast cancer survivors who are disease free at 5 years and relationship with low hormone receptor positivity. Br J Cancer. 2018;118(1):17-23
  2. Klauber-DeMore N, Schulte BA, Wang GY. Targeting MYC for triple-negative breast cancer treatment. Oncoscience. 2018;5(5-6):120-1.
  3. Scognamiglio R, Cabezas-Wallscheid N, Thier MC, Altamura S, Reyes A, Prendergast AM, et al. Myc Depletion Induces a Pluripotent Dormant State Mimicking Diapause. Cell. 2016;164(4):668-80