TBX3 over-expression causes mammary gland hyperplasia and increases mammary stem-like cells in an inducible transgenic mouse model

In this study, we created doxycycline inducible double transgenic mice (MMTV-rtTA;tet-myc-TBX3-IRES-Luciferase) to test whether TBX3 over-expression can induce tumor formation within the mammary gland. Although over-expression of TBX3, alone, did not induce tumor formation it did promote accelerated mammary gland development by increasing mammary epithelial cell proliferation. We also show that TBX3 directly binds to and represses NFκBIB, an inhibitor of the NF-κB pathway known to play a role in regulating cell proliferation. Lastly, we also show that the over-expression of TBX3 is associated with an increase in mammary stem-like cells.Overall, our data suggests that over-expression of TBX3 may contribute to breast cancer development by promoting accelerated mammary gland development through the inhibition of the NF-κB pathway and stimulation of both mammary epithelial cell and stem-like cell proliferation.TBX3 is a member of the T-box family of genes. T-box genes are expressed during embryonic development and have been found to regulate cell specification and organogenesis [1,2]. They are also well-known for the roles they play in many human developmental syndromes [3-6]. Tbx3 is known to function as a transcriptional repressor and is required for embryonic development and for the normal development of the mammary gland [7-11]. In mice models, homozygous mutations in which the function of Tbx3 is completely lost are embryonic lethal while haploinsufficiency of Tbx3 results in significantly reduced branching of ductal trees in adult animals [12]. In humans, mutations that result in the haploinsufficiency and loss of function of TBX3 ultimately cause Ulnar Mammary Syndrome (UMS) [3,13,14]. UMS is an autosomal dominant disorder characterized by mammary gland hypoplasia and affects limb, apocrine-gland, teeth, hair, and genital development. Besides Tbx3's role in early mammary gland development, various studies have also supported a role for Tbx3 in breast cancer devel