High ID2 protein expression correlates with a favourable prognosis in patients with primary breast cancer and reduces cellular invasiveness of breast cancer cells

Abstract

ID proteins have been implicated in the regulation of cell proliferation and differentiation in various cell types during normal development as well as in the formation of cancer. Our aim was to delineate the expression of ID2 by immunohistochemistry in primary breast cancer in order to detect potential associations with cell cycle regulatory proteins and/or clinicopathologic parameters. We further overexpressed ID2 in a breast cancer cell line to elaborate potential effects on proliferation and invasiveness. We observed large variations in ID2 expression in primary breast cancer, and the protein was localised to both the nucleus and cytoplasm. Interestingly, a high cytoplasmic ID2 protein level correlated with a favourable prognosis. Overexpressing ID2 in the MDA-MB-468 breast cancer cell line generated a marked cytoplasmic localisation of the protein and reduced the invasive capacity of cells. Modest enhancement of cell proliferation was further detected in ID2-overexpressing cells. In conclusion, ID2 protein expression varies substantially within primary breast tumours and high cytoplasmic levels of ID2 might reflect a less aggressive breast tumour phenotype. ' 2005 Wiley-Liss, Inc.Key words: ID2; breast cancer; proliferation; invasion The cell cycle regulatory machinery is a highly complex and delicate system that often is abrogated in cancer, and tumour cells consequently override one or more cell cycle checkpoints. One important checkpoint is the G 1 -S transition, where cells are committed to DNA replication and subsequent division. The cell cycle regulatory machinery is dependent on the activity of different CDKs and their associated cyclins, whose expression is tightly regulated over the cell cycle. Regulators of kinase activity are inhibitory proteins like p21, p27 and p16. One of the major substrates for the CDKs is pRb. Overexpression or inactivation of cell cycle regulatory proteins leads to abnormal proliferation and lack of checkpoint control. For example, inactivation of pRb has been noted in about 60% of all human cancers either by mutation and gene deletions or by deregulated phosphorylation, sequestration by oncoproteins or loss of cooperating factors.ID2 is a multipotent regulatory molecule harbouring an HLH motif. Through the HLH domain, ID proteins (ID1-ID4 in mammals) bind and sequester the DNA binding bHLH proteins known as E proteins, thereby preventing them from binding DNA alone or in complex with tissue-specifically expressed bHLH proteins. Since these latter bHLH proteins often are associated with differentiation and decreased proliferation, elevated ID protein levels often lead to maintained proliferation, whereas decreased ID protein levels are associated with differentiation.In the normal mammary epithelium, ID2 has been linked to critical steps in the development of functional mammary glands.2 The phenotype of homozygous ID2 knockout mice reveals lactation defects due to poor expansion of lobulo-alveolar tissue in the mammary glands, possibly caused by decreased proliferation of...

Sustained trophism of the mammary gland is sufficient to accelerate and synchronize development of ErbB2/Neu-induced tumors

“…Several (Idb2, Tpd52, Ghr, Ppp2r) of the 32 genes identified by both approaches have previously been associated with human breast cancer (Calin et al, 2000;Gebre-Medhin et al, 2001;Boutros et al, 2004;Stighall et al, 2005), corroborating this method for identifying genes involved in early stages of mammary gland tumorigenesis. In addition, 44% of the genes identified by this approach have known roles in cellular metabolism.…”

Id-1 and Id-2 are markers for metastasis and prognosis in oesophageal squamous cell carcinoma

“…In breast cancer, Id-2 expressed at high levels maintains the cancer cells in a non-aggressive phenotype ). In addition, high level of Id-2 expression has been shown to reduce the invasiveness of breast cancer cells and can act clinically as a favourable prognostic marker (Stighall et al, 2005). Similar results have been obtained in intestinal epithelium where Id-2 promotes differentiation and inhibit tumorigenesis (Russell et al, 2004).…”

“…Id-1 has also been shown to promote metastasis through increasing invasiveness and angiogenesis in breast and prostate cancer (Fong et al, 2003;Ling et al, 2005). High level of Id-2 has been demonstrated to reduce breast cancer cells invasiveness and therefore could act as a favourable prognostic marker for breast cancer patients (Stighall et al, 2005). In addition, the methylation status of Id-4 has been shown to correlate with poor prognosis in colorectal cancer (Umetani et al, 2004).…”

Expression profiling correlates with treatment response in women with advanced serous epithelial ovarian cancer

“…Recent studies have identified a nucleocytoplasmic shuffling of ID2 in vitro 48 and a favorable prognosis in breast cancer patients showing higher ID2 expression in the cytoplasm. 49 The relevance of this preliminary finding should be extended to a larger study, to further examine any relationship between ID2 localization and outcome in of late-stage ovarian cancer patients. Regardless of the role of these genes in the development of ovarian cancer, the combination of DCN and ID2 was able to significantly distinguish between participants with good or poor medium-term prognosis.…”