Fig. 7: Expression of MUC1-C in HR+/HER2− BCs with ESR1 mutations and refractory to CDK4/6 inhibitor treatment.

a Kaplan–Meier analysis of the TCGA BRCA Luminal B dataset for progression-free survival as a function of MUC1-high vs. MUC1-low tumors. b Representative examples of apical membranous, diffuse membranous and cytoplasmic staining for MUC1-C by IHC. Scale bar: 50 μm. c–e IHC score of MUC1-C levels on membranous, cytoplasmic or apical membranous regions were scored as 0, 1+, 2+ or 3+ based on the highest intensity occupying ≥10% of the evaluated area. The representative IHC score for HR+/HER2− (n = 18) (c), ESR1 mutant (n = 11) (d) and CDK4/6 inhibitor resistant (n = 5) (e) BCs was determined by adopting the maximum score of each region. f IHC staining for MUC1-C expression of a HR+/HER2− BC metastatic to pleura pre-treatment (left) and post-treatment with ET in combination with CDK4/6 inhibition in a setting of progressive disease (right). Scale bar: 100 μm. g Schema depicting MUC1-C-mediated regulation of ER signaling in ER wild-type, ER mutant and CDK4/6 inhibitor resistant cells. Our results demonstrate that MUC1-C forms nuclear complexes with SRC-3 and MED1 and that targeting MUC1-C genetically and pharmacologically decreases SRC-3 and MED1 expression. Importantly, we further show that targeting MUC1-C suppresses ER, SRC-3 and MED1 levels in chromatin. We also demonstrate mechanistically that MUC1-C is necessary for expression of (i) MK2, which stabilizes SRC-3, and (ii) CDK7, which stabilizes MED1. These findings uncover the previously unrecognized role of MUC1-C in regulating SRC-3 and MED1 as effectors of drug resistance. Identification of this common pathway in drug-resistant HR+/HER2− BC cells formed the basis for the findings that an anti-MUC1-C ADC is effective for their treatment.