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Abstract Background Menopausal hormone therapy (MHT) is recommended for only five years to treat vasomotor symptoms and vulvovaginal atrophy because of safety concerns with long-term treatment. We investigated the ability of 2′,3′,4′-trihydroxychalcone (2′,3′,4′-THC) to modulate estrogen receptor (ER)-mediated responses in order to find drug candidates that could potentially prevent the adverse effects of long-term MHT treatment. Methods Transfection assays, real time-polymerase chain reaction, and microarrays were used to evaluate the effects of 2′,3′,4′-THC on gene regulation. Radioligand binding studies were used to determine if 2′,3′,4′-THC binds to ERα. Cell proliferation was examined in MCF-7 breast cancer cells by using growth curves and flow cytometry. Western blots were used to determine if 2′,3′,4′-THC alters the E2 activation of the MAPK pathway and degradation of ERα. Chromatin immunoprecipitation was used to measure ERα binding to genes. Results The 2′,3′,4′-THC/E2 combination produced a synergistic activation with ERα on reporter and endogenous genes in human U2OS osteosarcoma cells. Microarrays identified 824 genes that we termed reprogrammed genes because they were not regulated in U2OS-ERα cells unless they were treated with 2′,3′,4′-THC and E2 at the same time. 2′,3′,4′-THC blocked the proliferation of MCF-7 cells by preventing the E2-induced activation of MAPK and c-MYC transcription. The antiproliferative mechanism of 2′,3′,4′-THC differs from selective estrogen receptor modulators (SERMs) because 2′,3′,4′-THC did not bind to the E2 binding site in ERα like SERMs. Conclusion Our study suggests that 2′,3′,4′-THC may represent a new class of ERα modulators that do not act as a direct agonists or antagonists. We consider 2′,3′,4′-THC to be a reprogramming compound, since it alters the activity of ERα on gene regulation and cell proliferation without competing with E2 for binding to ERα. The addition of a reprogramming drug to estrogens in MHT may offer a new strategy to overcome the adverse proliferative effects of estrogen in MHT by reprogramming ERα as opposed to an antagonist mechanism that involves blocking the binding of estrogen to ERα.