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To unravel the mechanisms underlying failure of endocrine therapy of breast cancer, we have previously executed a functional genetic screen and identified the adaptor protein BCAR1 to be causative for tamoxifen resistance. As a consequence of the manifold of interactions with other proteins, we characterized the contribution of individual protein domains of BCAR1 to anti-estrogen-resistant proliferation of human breast cancer cells. We took advantage of the observation that the closely related family member HEF1 was unable to support long-term anti-estrogen-resistant cell proliferation. Chimerical proteins containing defined domains of BCAR1 and HEF1 were evaluated for anti-estrogen-resistant growth. Exchange of the SH3 and C-terminal domains did not modify the capacity to support cell proliferation. Full support of anti-estrogen resistant proliferation was observed for chimerical molecules containing the central part of BCAR1. The bi-partite SRC-binding site or the Serine-rich domain did not explain the differential capacity of BCAR1. These findings indicate that the differences between BCAR1 and HEF1 with respect to support of anti-estrogen resistance reside in the substrate domain which contains multiple sites for tyrosine phosphorylation. The crucial interactions required for anti-estrogen resistance occur within the substrate domain of BCAR1. Further deciphering of these interactions may resolve the growth regulatory mechanism and provide an explanation for the observation that primary tumors with high levels of BCAR1 are likely to fail on tamoxifen therapy. This information may also help to devise alternative personalized treatment strategies with improved outcome for breast cancer patients.