The Pbx proteins belong to the PBC group of TALE proteins able to cooperatively bind to DNA with Hox proteins of paralogy groups 1�C10. In vitro studies have shown that Hox/Pbx heterodimers display a greater affinity and specificity for cognate DNA sequences than the Hox monomers . The interaction between Hox proteins of paralog groups 1�C8 and Pbx purchase Gefitinib relies on a conserved hexapeptide sequence located N-terminal to the Hox homeodomain and sharing core Tryptophan and Methionine residues. Hox proteins of paralog groups 9 and 10 do not contain this hexapeptide, they only present a conserved Tryptophan allowing their interaction with Pbx . Mutational analysis of Hoxa1 has revealed that the Tryptophan and Methionine residues of the conserved hexapeptide are critical for the cooperative interaction between Hoxa1 and Pbx1 . Moreover, the mutant Hoxa1 protein was found to be inactive on cognate target enhancers in live cells . Finally, in vivo studies have demonstrated that knock-in mice for mutations resulting in a WM-to-AA substitution in the hexapeptide of Hoxa1 display hindbrain, cranial nerve and skeletal defects corresponding to the phenotype of the Hoxa1 knock-out . Together, these data support that the embryonic function of Hoxa1 requires the integrity of its hexapeptide motif, which in turn suggests that the activity of the protein critically relies on its partnership with Pbx. Considering the requirement for an intact hexapeptide for the normal activity of Hoxa1, we have addressed here its importance for the oncogenic potential of the protein. Proliferation, anchorageindependent growth and foci assays have been performed to compare the cellular responses to wild-type or hexapeptide mutant Hoxa1. Our data demonstrate that the WM-to-AA substitution in the Hoxa1 hexapeptide severely impairs its oncogenic properties, which therefore suggests the Hoxa1/Pbx partnership to be involved in its ability to transform mammary epithelial cells. Possible implications in terms of therapeutic applications are discussed. Hoxa1 has previously been shown to affect the phenotype of the epithelioid mammary tumor cell line MCF7 in a way that is indicative of its pro-oncogenic activity, as its forced expression enhanced cell proliferation and anchorage-independent growth .