The Role of single minded 2 short in mammary gland development and breast cancer
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Single minded 2 (Sim2) is a member of the basic helix-loop-helix Per-ARNT-Sim (Period-Arylhydrocarbon Nuclear Translocator-Single minded) family. Human SIM2 is involved in the etiology of the Down?s phenotype. In addition to the physical and mental deficiencies associated with DS, it has become apparent that women with DS are 10-25 times less likely to develop breast cancer in comparison to age-matched normal populations. Such significant effects on breast cancer susceptibility are thought to result from gene dosage effects of one or more tumor suppressor genes on chromosome 21. Here we report the identification and transcriptional characterization of mouse Sim2s, a splice variant of Sim2, which is missing the carboxyl Pro/Ala-rich repressive domain. Similar to full-length Sim2, Sim2s interacts with ARNT and to a lesser extent, ARNT2. The effects of Sim2s on transcriptional regulation through hypoxia-, dioxin- and central midline response elements are different than that of full length Sim2. Specifically, Sim2s exerts a less repressive effect on hypoxia-induced gene expression than full length Sim2, but is just as effective as Sim2 at repressing TCDD-induced gene expression from a dioxin response element. Interestingly, Sim2s binds to and activates expression from a central midline response element-controlled reporter through an ARNT transactivation domain-dependent mechanism. Forced expression of SIM2s in MDA-MB-435 breast cancer cells significantly inhibited proliferation, reduced anchorage-independent growth, and decreased invasive potential. SIM2s directly decreased expression of matrix metalloprotease-3, a known mediator of breast cancer metastasis. In addition, loss of Sim2 in the mouse mammary gland increased ductal branching, accelerated lobuloalveolar-like precocious hyperplasia, and decreased cell apoptosis, suggesting that SIM2s is a mammary tumor suppressor. Sim2-/- mammary glands lose E-cadherin expression, suggesting that Sim2s plays a role in regulating E-cadherin/beta-catenin signaling. Loss of Sim2 in the mammary glands also resulted in dramatically increased MMP3 expression. The mechanism of SIM2smediated repression of MMP3 was found to be due to its ability to inhibit AP-1 binding to the MMP3 promoter. These results suggest that SIM2s contributes to the breast cancer protective effects observed in DS individuals.