TARGETING HOXB13-OVEREXPRESSING TAMOXIFEN-RESISTANT BREAST CANCER

tamoxifen-resistance;HOXB13;Human Genetics and Molecular Biology

Cruz, Leigh-AnnKinzler, Kenneth ;

Johns Hopkins University

关键词: tamoxifen-resistance;    HOXB13;    Human Genetics and Molecular Biology;   

Others  :  https://jscholarship.library.jhu.edu/bitstream/handle/1774.2/60318/CRUZ-DISSERTATION-2014.pdf?sequence=1&isAllowed=y

瑞士|英语

来源: JOHNS HOPKINS DSpace Repository

【 摘 要 】

Aberrant expression of the homeobox (HOX) gene family of transcription factors has been implicated in the development of many different cancers, including breast.The high ratio of homeobox 13 (HOXB13) to interleukin-17-β receptor (IL17BR) expression has been found to be associated with increased relapse, tumor aggressiveness, tamoxifen (TAM) treatment failure, and death in breast cancer patients.For nearly a decade, HOXB13 has been known as an effective biomarker of TAM resistance (TAMR), however its role in the disease was unclear.Our recent studies established that HOXB13 overexpression promotes TAMR as well as stromal invasion and metastasis via interleukin-6 (IL6) upregulation due to increased signaling of its pathway and subsequent stromal-tumor crosstalk.In order to identify other potential, targetable mechanisms of HOXB13-mediated TAMR, we used a two-pronged approach to our goal, the first, using microarray analysis to discover new targets associated with HOXB13-expression in our cell line models, and the second, to interrogate other aspects of the IL-6 pathway that can possibly be more accessible, more effective targets to inhibit HOXB13-mediated-TAMR.Although our microarray studies did not yield novel targets of HOXB13-expressing TAMR, investigating other aspects of IL6 action in our HOXB13-expressing cell line models via inhibition of these downstream effectors found the anti-IL6R antibody tocilizumab (TOC) to specifically inhibit HOXB13-expressing tumor growth both in vitro and in vivo, as well as abrogate the stromal desmoplastic response typical of our HOXB13-overexpressing xenografts and of aggressive tumors.These data suggest TOC to be a promising therapy able to specifically target HOXB13-expressing TAMR breast cancer, leading to more effective options for the treatment of TAMR, as well as a better understanding of the function and mechanism of the role of HOXB13 in this disease.