ID genes mediate tumor reinitiation during breast cancer lung metastasis

Abstract

The establishment of distant metastases depends on the capacity of small numbers of cancer cells to regenerate a tumor after entering a target tissue. The mechanisms that confer this capacity remain to be defined. Here we identify a role for the transcriptional inhibitors of differentiation Id1 and Id3 as selective mediators of lung metastatic colonization in the triple negative [TN, i.e., lacking expression of estrogen receptor and progesterone receptor, and lacking Her2 (human epidermal growth factor receptor 2) amplification] subgroup of human breast cancer. Although broad expression of Id1 has recently been documented in tumors of the rare metaplastic subtype, here we report that rare Id1-expressing cells are also present in the more common TN subset of human breast tumors but not in other subtypes. We also provide evidence that Id1 expression is enriched in clinically obtained hormone receptor negative lung metastases. Functional studies demonstrate that Id1 and its closely related family member Id3 are required for tumor initiating functions, both in the context of primary tumor formation and during metastatic colonization of the lung microenvironment. In vivo characterization of lung metastatic progression reveals that Id1 and Id3 facilitate sustained proliferation during the early stages of metastatic colonization, subsequent to extravasation into the lung parenchyma. These results shed light on the proliferative mechanisms that initiate metastatic colonization, and they implicate Id1 and Id3 as mediators of this malignant function in the TN subgroup of breast cancers.proliferation ͉ stem cells ͉ triple negative

Identification of Staphylococcal Nuclease Domain-containing 1 (SND1) as a Metadherin-interacting Protein with Metastasis-promoting Functions

“…Specifically, several genes validated to promote different aspects of lung metastasis resided in the enrichment core of lung metastasis genes with the most significant elevation of expression in SND1-expressing control cells as compared with SND1-KD cells. For example, TGF-␤-induced ANGPTL4 has been shown to enhance extravasation of breast cancer cells in lung metastasis (41), EREG has been shown to promote extravasation and lung colonization (42), and Id1 functions to promote the tumor initiation stage of lung metastasis colonization (40). KiSS1, although not part of the lung metastasis signature, has nonetheless been reported to repress metastasis (to the lung and other organs) in many tumor types.…”

ID1 Facilitates the Growth and Metastasis of Non-Small Cell Lung Cancer in Response to Nicotinic Acetylcholine Receptor and Epidermal Growth Factor Receptor Signaling

“…It has been shown that ID1 was essential for the metastasis of cancers to the lung in mouse models of cancer (13,18). Studies on cultured cells and mouse models have shown that levels of ID1 correlate with invasive as well as metastatic properties of cancer cells and that transfection of ID1 could make human breast cancer cells significantly more aggressive and metastatic (32).…”

Id1 Is Down-Regulated by Hepatocyte Growth Factor via ERK-Dependent and ERK-Independent Signaling Pathways, Leading to Increased Expression of p16INK4a in Hepatoma Cells

“…of differentiation, which results in an arrest of cell proliferation, decreases Id1 levels (26)(27)(28). Also, ectopic expression of Id1 accelerates cell proliferation (59), and Id1 is involved in cellular transformation, which enables cells to progressively proliferate despite any signal for the inhibition of cell proliferation (24,60,61). These results indicate the importance of Id1 to the regulation of cell proliferation and suggest that the levels of Id1 are partly responsible for the difference in the effect of HGF on cell proliferation.…”