Posted October 13, 2015
Xiaosong Wang, M.D., Ph.D., and Rachel Schiff, Ph.D., Baylor College of Medicine

Drs. Xiaosong Wang and Rachel Schiff Approximately 70% of all breast cancers are estrogen receptor-positive (ER+). The most common way to treat ER+ cancers is through endocrine therapy, which includes drugs like tamoxifen that block estrogen from binding to the receptor. However, many ER+ breast tumors treated with endocrine therapy will relapse; therefore, understanding the mechanism of tumor resistance and identifying new therapeutic targets are critical to improving patient outcomes.

Dr. Xiaosong Wang and Dr. Rachel Schiff, with support from BCRP and Breast Cancer Stamp funding, collaborated to study genomic rearrangements in ER+ breast cancer. Genomic rearrangements involving translocation of genes could result in gene fusions and characteristic copy number alterations. By studying genomic data in the Cancer Genome Atlas and creating a tool called Fusion Zoom to process this data (, Drs. Wang and Schiff were able to identify a gene fusion that is more prevalent in the more aggressive luminal B subtype of ER+ tumors. This gene fusion, ESR1-CCDC170, combines the estrogen receptor gene and CCDC170, whose function is unknown. Further studies showed that the protein product of this gene fusion reduced endocrine sensitivity and increased the movement and metastatic potential of ER+ breast cancer cells. This newly identified gene fusion may lead to a better understanding of the genetic origin of aggressive ER+ breast cancers and may provide a new therapeutic target for effective intervention.

Additionally, the investigators validated and identified the roles of tousled-like kinase 2 (TLK2) and Nemo-Like Kinase (NLK). When TLK2 was overexpressed in cells, correlating genomic instability was observed and DNA repair was disrupted. The cells also become more invasive. The investigators showed that inhibiting TLK2 blocked breast cancer tumor growth in mice and determined that TLK2 may be a potential new target for aggressive ER+ breast cancers. In addition, they discovered a crucial role of NLK in a previously unknown survival signaling pathway that endows endocrine resistance of breast cancer cells. Studies showed that when the amount of NLK in endocrine therapy-resistant cancer cells was inhibited, responsiveness to endocrine therapy (tamoxifen) was restored. They also identified a potent NLK inhibitor which has already undergone phase I and II clinical trials for treating inflammatory disease, and investigated its therapeutic potential in endocrine-resistant ER+ breast cancer cells. The NLK inhibitor was able to sensitize the cancer cells to tamoxifen treatment thus precipitating cell death. Further, through collaborations they also facilitated the identification of a third kinase target called MAP3K3 that appears to endow resistance of breast cancer cells to cytotoxic chemotherapy. With these studies, Drs. Wang and Schiff identified three novel kinase targets for more aggressive breast cancers and, moreover, have identified a promising drug against one of those targets.


Veeraraghavan J, Tan Y, Cao XX, Kim JA, Wang X, Chamness GC, Maiti SN, Cooper LJN, Edwards DP, Contreras A, Hilsenbeck SG, Chang EC, Schiff R, and Wang XS. 2014. Recurrent ESR1-CCDC170 rearrangements in an aggressive subset of estrogen-receptor positive breast cancers. Nature Communications 5:4577 doi: 10.1038/ncomms5577.

Fan Y*, Ge N*, Wang XS*, Sun W*, Mao R, Bu W, Creighton CJ, Zheng P, Vasudevan S, An L, Yang J, Zhao YJ, Zhang H, Li XN, Rao PH, Leung E, Lu YJ, Gray JW, Schiff R, Hilsenbeck SG, Osborne CK, Yang J, Zhang H. Amplification and overexpression of MAP3K3 gene in human breast cancer promotes formation and survival of breast cancer cells. The Journal of Pathology. 2014 232:75-86.

Xu QW, Zhao W, Wang Y, Sartor MA, Han DM, Deng JX, Ponnala R, Yang JY, Zhang QY, Liao GQ, QuYM, Li L, Liu FF, Zhao HM, Yin YH, Chen WF, Zhang Y, and Wang XS. 2012. An integrated genome-wide approach to discover tumor specific antigens as potential immunological and clinical targets in cancer. Cancer Research 72(24):6351-6361.


Public and Technical Abstracts: Copy Number Signature of Recurrent Gene Fusions Reveals Potential Drug Targets in Invasive Breast Cancer

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