Id-1 as a molecular target in therapy for breast cancer cell invasion and metastasis

Abstract

Mammary epithelial cells constitutively expressing Id-1 protein are unable to differentiate, acquire the ability to proliferate, and invade the extracellular matrix. In addition, Id-1 is aberrantly over-expressed in aggressive and metastatic breast cancer cells, as well as in human breast tumor biopsies from infiltrating carcinomas, suggesting Id-1 might be an important regulator of breast cancer progression. We show that human metastatic breast cancer cells become significantly less invasive in vitro and less metastatic in vivo when Id-1 is downregulated by stable transduction with antisense Id-1. Expression of the matrix metalloproteinase MT1-MMP is decreased in proportion to the decrease in Id-1 protein levels, representing a potential mechanism for the reduction of invasiveness. Further, to more accurately recapitulate the biology of and potential therapeutic approaches to tumor metastasis, we targeted Id-1 expression systemically in tumorbearing mice by using a nonviral approach. We demonstrate significant reduction of both Id-1 and MT1-MMP expressions as well as the metastatic spread of 4T1 breast cancer cells in syngeneic BALB͞c mice. In conclusion, our studies have identified Id-1 as a critical regulator of breast cancer progression and suggest the feasibility of developing novel therapeutic approaches to target Id-1 expression to reduce breast cancer metastasis in humans.T he Id (inhibitor of DNA binding) genes were originally identified in murine myoblasts, where they prevented myogenic basic helix-loop-helix (bHLH) transcription factors from binding muscle-specific regulatory elements (1). These transcription factors are key regulators of tissue-specific gene expression in a number of mammalian and nonmammalian organisms, and constitutive expression of Id proteins has been shown to inhibit the differentiation of various tissues (2). bHLH proteins act as obligate dimers, dimerizing through HLH domains, and bind to DNA through the composite basic domains to activate the transcription of target genes containing E-boxes (CANNTG) in their promoters. Id proteins dimerize with bHLH proteins, but the Id-bHLH heterodimers fail to bind to DNA because Id proteins lack the basic domains necessary for DNA interaction.Four members of the Id gene family have been described to date: Id-1, . The different family members localize to different chromosomes and show marked differences in their pattern of expression and function (3, 4). Although the family members are similar in the HLH sequence, the regions outside the HLH domain are distinct for each member and may determine the tissue specificity of Id function, as well as the binding specificity for particular bHLH proteins.We previously developed a line of murine mammary epithelial cells (MEC), SCp2 cells, which originated from a midpregnant mouse mammary gland (5, 6). A role for HLH Id proteins in the differentiation of SCp2 cells was suggested by our finding that Id-1 expression declined to undetectable levels when the cells were induced to differentiate in culture ...

Reassessment of Id1 Protein Expression in Human Mammary, Prostate, and Bladder Cancers Using a Monospecific Rabbit Monoclonal Anti-Id1 Antibody

“…Mobilization of endothelial cell progenitors from the bone marrow is also severely perturbed in Id knockout mice consistent with this hypothesis (10,11). On the other hand, a role for Id1 in modulating tumor epithelial cell behavior is suggested by the fact that overexpression of Id1 in cell lines results in increased invasiveness and metastatic potential of these cells, whereas reduction of high levels of Id1 present endogenously in these lines leads to an inhibition of these properties (12)(13)(14)(15)(16)(17).…”

High-risk human papillomavirus infections in breast cancer in Syrian women and their association with Id-1 expression: a tissue microarray study

“…Moreover, we demonstrated that E6/E7 onco-proteins of HPV type 16 convert non-invasive breast cancer cells to an invasive phenotype (Yasmeen et al, 2007a); this is accompanied by an overexpression of Id-1, which regulates cell invasion and metastasis of human breast cancer cells (Desprez et al, 1998;Fong et al, 2003). In this study, we investigated the relation between high-risk HPVs and Id-1 expression in breast cancer tissues from Syrian women.…”

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

“…Id-1 has been shown to promote metastasis in several different types of cancer. Overexpression of Id-1 promotes mammary epithelial cell invasion (Desprez et al, 1998), and reduced expression of Id-1 in metastatic breast cancer cells leads to a decrease in invasiveness in vitro (Fong et al, 2003). Overexpression of Id-1 in prostate cancer cells also promotes metastasis through increased angiogenesis and invasiveness (Coppe et al, 2004).…”

“…For instance, a high-level expression of Id-1 has been shown to be associated with poor prognosis of early-stage cervical cancer (Schindl et al, 2001), node-negative breast cancer (Schoppmann et al, 2003) and malignant melanoma (Straume and Akslen, 2005). 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).…”