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. Author manuscript; available in PMC: 2021 Jul 1.
Published in final edited form as: Mol Cancer Ther. 2020 Nov 11;20(1):11–25. doi: 10.1158/1535-7163.MCT-20-0563

Figure 10. Schematic representation of the study’s conclusions highlighting major ER coactivator-binding differences in MCF-7:5C between E2, E4, ShERPAs, and BPTPE, and with ShERPA TTC-352 between WT MCF-7:WS8 and LTED endocrine-resistant MCF-7:5C BC.

Figure 10.

A, E2, E4, ShERPA BMI-135, ShERPA TTC-352, and BPTPE major ER coactivators’ recruitment, and anti-tumor molecular mechanism in MCF-7:5C. E2:ERα and E4:ERα complexes mainly recruit NCOA3, KMT2D, and many of the same MEDs, and induce a high threshold of stress; through the synthesis of unfolded and/ or misfolded proteins, leading to rapid apoptosis. TTC-352 (referred to as TT in the illustration) recruited more MED subunits than E2, but less NCOA3 and KMT2D than E2 and E4, with a similar threshold of stress and timing of apoptosis to E2 and E4. BMI-135 (referred to as BM in the illustration) recruited less NCOA3 and KMT2D than E2 and E4, and shared MED subunit recruitment with E4, which generated a lower threshold of stress and delayed apoptosis (48) compared to E2, E4, and TTC-352. BPTPE (referred to as BP in the illustration) did not have much of a coactivator-recruitment, which generates a very low threshold of stress and a much more delayed course of apoptosis (48) compared to E2, E4, TTC-352, and BMI-135. This differential ligand:ERα:coactivator-reucitment-and-induced EnR stress, sets the therapeutics apart, in terms of the timing of activating the UPR, followed by inducing apoptosis. The box (in gray) highlights the observed recruitment patterns: thick arrow (in red) represents relatively more recruitment, thin arrow (in burgundy) is relatively less recruitment, thin arrow (in burgundy with green border) is shared subunit recruitment, and thin arrow (in blue) is no recruitment. B, TTC-352’s paradoxical effect in WT growth-inducing BC MCF-7:WS8 versus LTED apoptosis-inducing BC MCF-7:5C. NCOA3, KMT2D, and many MEDs (especially MED12-16 and MED23) are recruited to ER, in MCF-7:5C treated with TTC-352 (thick arrow in maroon), compared to E2, but these same coactivators are reduced upon the treatment of MCF-7:WS8 with TTC-352 (thin arrow in rose). This differential ligand:ERα:coactivator-reucitment-and-induced EnR stress, phenotypically sets the two BC models apart.