Abstract IA6: Epithelial-mesenchymal plasticity in breast cancer metastasis
Authors: Kang Yibin 
Published: August 2014

Abstract
Increasing evidence suggests that the normal genetic programs underlying various developmental processes can often be usurped in pathological conditions such as cancer metastasis. Epithelial—mesenchymal transition (EMT) is a complex process that is associated with dramatic changes in cell adhesion, polarity, and migratory properties, and is intimately associated both with cell fate transitions during embryonic development and with the acquisition of invasive properties during cancer metastasis. Several transcription factors, including the Snail, Zeb and Twist families, have been identified as major drivers of EMT by repressing the transcription of E-cadherin. However, our knowledge about the regulatory network and pleiotropic effects of epithelial-mesenchymal plasticity remains largely incomplete, and the importance of reverse process, mesenchymal-epithelial transition (MET), is poorly understood.
In our study of the early stage of breast cancer metastasis, we found that the transcription factor Elf5, a key regulator of alveologenesis in the mammary gland, regulates EMT in both mammary gland development and metastasis. This specific role for Elf5 in suppressing EMT and metastasis was uncovered via analyses of Elf5 conditional knockout animals, various in vitro and in vivo models of EMT and metastasis, an MMTV-neu transgenic model of mammary gland tumor progression, and clinical breast cancer samples. Furthermore, we demonstrate that this role of Elf5 is mediated by the direct transcriptional repression of Snail2/Slug, a master regulator of mammary stem cells and a known inducer of EMT. These findings establish a broad molecular function of Elf5 that extends from being a key cell lineage regulator during normal mammary gland development to serving as a suppressor of EMT and metastasis in breast cancer.
Focusing on non-coding RNAs as potential novel regulators of EMT, we identified the miR-200 family miRNAs as suppressors of EMT and tumor invasion that function via direct targeting of Zeb1 and Zeb2. Contrary to the expectation that miR-200s should inhibit metastasis, we found that miR-200 overexpression is in fact associated with poor metastasis-free survival of breast cancer patients and functionally promotes metastatic colonization in mouse models. Through an integrated genomic/proteomic analysis, we identified the Sec23a secretory pathway as a prominent functional target of miR-200s with an active role in suppressing metastatic colonization. Secretome analysis further identified IGFBP4 and TINAGL1 as important Sec23a-dependent secreted proteins with metastasis suppressive functions. Thus, the dichotomous functions of miR-200s in inhibiting early steps of invasion while promoting late step of metastatic colonization is achieved through targeting of both tumor cell-intrinsic and —extrinsic regulatory pathways. Taken together, these findings support dynamic and pleiotropic roles of epithelial-mesenchymal plasticity in early and late stages of metastatic progression: while EMT is necessary for initial invasion, MET may be required for efficient colonization.
Citation Format: Yibin Kang. Epithelial-mesenchymal plasticity in breast cancer metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr IA6.