Mechanism of LSD1 in breast cancer metastasis suppression

点击翻译按钮获取中文摘要

Comparisons of genetic mutations found in primary tumors and their corresponding metastatic lesions have so far failed to define genetic mutations that lead to metastasis. This raises a notion that it is the epigenetic mechanisms, working together with cancer type-specific oncogenic and/or cell type-specific lineage programs, that may drive metastatic progression. In breast cancer, how epigenetic abnormalities drive metastatic progression remains largely elusive. A better understanding of this may lead to novel strategies to block breast cancer metastasis. LSD1 (KDM1A) is the first identified histone demethylase. In human cancers, genetic abnormalities of LSD1 mainly include deletions and mutations. Such deletions/mutations have also been found in metastatic breast cancer, raising a possibility that LSD1 is a breast cancer metastasis suppressor. Indeed, in preliminary studies, we found induced loss of LSD1 in luminal mammary tumor cells or LSD1 inhibitor treatment in the MMTV-PyMT mouse model led to a dramatic increase in lung metastasis. Mechanistically, in luminal breast cells, we found LSD1 interacts with GATA3, a key luminal-specific transcription factor, to control their common programs related to cell-cell adhesion and cell cycle. LSD1 positively regulates GATA3 expression and represses that of TRIM37, a common target of both LSD1 and GATA3, which encodes a histone H2A ubiquitin ligase involved in gene repression. Importantly, TRIM37 may contribute to increased invasion and migration of luminal breast cancer cells with LSD1-loss via repression of several cell adhesion genes (e.g., CDH1, VCL, CTNNA1). Such expression changes were also observed in murine PyMT tumor cells with LSD1-loss. Together, these data suggest that LSD1 may suppress breast cancer metastasis via regulation of its target genes (e.g., TRIM37) in luminal cells in a demethylase activity- dependent manner. Intriguingly, PyMT tumor cells with LSD1 ablation also exhibited a profound change in immune-related genes, suggesting that LSD1 may also suppress breast cancer metastasis by a cell-extrinsic, immune-related mechanism. To test these, we will continue to establish mouse intraductal injection (MIND) transplantation models for PyMT tumor cells and human estrogen receptor+ breast cancer cell lines as our in vivo system. In Aim 1, we will perform CRISPR-based screens to map functional domain(s) of LSD1 responsible for its metastasis suppression vs. proliferation/survival-supporting roles, and test if LSD1 mutations found in patients impair its metastasis suppression function via disruption of the demethylase activity. In Aim 2, we will determine roles of LSD1 targets (e.g., TRIM37 and its partner EZH2, and others) of luminal cells at different steps of the metastatic cascade in various MIND models. In Aim 3, we will determine the immune mechanism mediating increased PyMT metastasis associated with LSD1 ablation, in particular, NK cells and MHC-I molecules, as LSD1-loss in PyMT tumor cells led to a profound upregulation of various classic and non-classic MHC-Is, which serve as ligands for inhibitory receptors in NK cells.