Epigenetic Repression of PDZ-LIM Domain-containing Protein 2

Abstract

The NF-B transcription factor plays a pivotal role in breast cancer progression and therapy resistance. However, the mechanisms by which the tightly regulated NF-B becomes constitutively activated during breast cancer pathogenesis remain obscure. Here, we report that PDZ-LIM domain-containing protein 2 (PDLIM2), an essential terminator of NF-B activation, is repressed in both estrogen receptor-positive and estrogen receptor-negative breast cancer cells, suggesting one important mechanism for the constitutive activation of NF-B. Indeed, PDLIM2 reexpression inhibited constitutive NF-B activation and expression of NF-B-targeted genes in those breast cancer cells. Importantly, PDLIM2, but not its mutants defective in NF-B termination, could suppress in vitro anchorage-independent growth and in vivo tumor formation of those malignant breast cells. In addition, we have shown that PDLIM2 repression involves promoter methylation. Accordingly, treatment of the breast cancer cells with the DNA methyltransferase inhibitor 5-aza-2-deoxycytidine reverses the methylation of the PDLIM2 promoter, restored PDLIM2 expression, and suppressed tumorigenicities of human breast cancer cells both in vitro and in vivo. These studies thus provide important mechanistic insights into breast cancer pathogenesis. These studies also suggest a tumor suppression function of PDLIM2 and a therapeutic strategy for breast cancer.Breast cancer has the highest incidence among women in the Western world, affecting more than 12% of women and accounting for 15% of all cancer deaths in women (1). In addition, although breast cancer is relatively rare in men, both the incidence and the death rate of male breast cancer remain one percentile compared with those of female breast cancer. The limitation on better treatments for this malignancy is largely due to lack of knowledge on the molecular mechanism of how breast cancer proceeds to become an invasive tumor that is resistant to cancer therapies.Recent studies have suggested that NF-B, a transcription factor essential for inflammatory and immune response, plays a pivotal role in the biology and therapy resistance of breast cancer (2-4). For example, constitutive activation of its prototypic member RelA/p65 has been shown to be important for the development and progression of breast cancer and therefore resistant to cancer therapies (5, 6). However, NF-B activation is tightly controlled under physiological conditions (7). In resting, nonstimulated cells, NF-B is sequestered in the cytoplasm by specific inhibitors, the IB proteins (mainly IB␣). In response to a variety of stimuli, including microbial infection and proinflammatory cytokines, the NF-B-bound IB␣ is quickly phosphorylated, ubiquitinated, and degraded, allowing liberated NF-B to enter the nucleus for gene transcription. Besides induction of proinflammatory cytokines, and cell proliferation and survival genes, nuclear NF-B also induces expression of IB␣, which in turn enters the nucleus and shuttles the activated NF-B back to the cytoplasm to reco...

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