In mice models, homozygous mutations in which the function of Tbx3 is completely lost are embryonic lethal while haploinsufficiency of Tbx3 results in signifi cantly reduced branching of ductal trees in adult ani mals. In humans, mutations that result in the haploinsufficiency and loss of function selleckchem Seliciclib of TBX3 ulti mately cause Ulnar Mammary Syndrome. UMS is an autosomal dominant disorder char acterized by mammary gland hypoplasia and affects limb, apocrine gland, teeth, hair, and genital develop ment. Besides Tbx3s role in early mammary gland development, various studies have also supported a role for Tbx3 in breast cancer development. The TBX3 gene is located at the 12q24 region which is frequently ampli fied in a variety of malignancies including breast cancer.
Moreover, TBX3 is over expressed in various breast cancer cell lines as well as primary breast cancer tissues. TBX3 is mislocalized to the cytoplasm in primary breast cancer tissues and serum TBX3 protein levels were also found to be abnormally high in early stage breast cancer patients. More recently, it has been shown that PMA induced up regulation of TBX3 contributes to breast cancer cell migration. TBX3 has been shown to repress the expression of the tumor suppression gene p14ARF and the mur ine homologue p19ARF. The p14 19 Mdm2 p53 pathway plays an important role in regulating cell senes cence and protects cells against oncogenic transforma tion which leads to tumor formation. TBX3 over expression has been shown to immortalize mouse embryonic fibroblast cells by suppressing p19ARF.
We have previously shown that over expres sion of TBX3 represses human p14ARF by recruiting HDAC 1, 2, 3 and 5 in the MCF7 breast cancer cell line. In order to identify other targets of TBX3, we used chromatin immunoprecipitation guided ligation and selection promoter array. Our results showed that 430 gene promoters are bound by TBX3 in the MCF7 breast cancer cell line. One of the identified genes, NF BIB, is an inhibitor of NF B. Studies have shown that NF B associated path ways play an important role in cell proliferation, differ entiation and apoptosis. Specifically, NF BIB inhibits NF B by sequestering it in the cytoplasm. Acti vation of NF B occurs upon ubiquitin mediated degra dation of NF BIB proteins via serine phosphorylation by I B kinase.
Studies have shown that inhibition of NF B activation in mouse mammary glands lead to defective proliferation in lobuloalveolar structures dur Anacetrapib ing pregnancy, whereas elevated NF B activity causes mammary hyperplasia in vivo. Furthermore, aberrant activation of NF B is related to breast cancer progression, including tumor initiation, proliferation, chemoresistance and tumor metastasis. Taken together, these studies suggest that a dysregulation of TBX3 expression may contribute to breast cancer development.
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