Abstract Approximately half of all HER2+ breast cancers are hormone receptor positive (HR+) and express estrogen and/or progesterone receptors (ER, PR). These HR+/HER2+ tumors are less responsive to neoadjuvant anti-HER2 therapy and exhibit lower rates of pathologic complete response (pCR). While HER2 primarily functions as a transmembrane receptor that mediates cytoplasmic signaling, a subpopulation of HER2 resides in the nucleus. Prior studies have shown that chromatin-associated HER2 can serve as a transcriptional co-regulator, and its presence in tamoxifen-treated, ER+ (non-HER2-amplified) breast cancer correlates with shorter disease-free survival. We therefore hypothesized that nuclear HER2 may reprogram ER function in HR+/HER2+ breast cancer, thereby contributing to reduced pCR rates. In multiple HR+/HER2+ cell line models, low baseline levels of nuclear HER2 are rapidly increased following treatment with the monoclonal antibodies trastuzumab and pertuzumab (TP). While TP does not alter nuclear ER levels, it enhances ER recruitment to promoter and enhancer regions of TFF1 and PGR (two classical ER target genes) and upregulates their mRNA levels in HR+/HER2+, but not in ER+ only breast cancer cells. To define the global impact of TP treatment on the ER cistrome, we performed Cleavage Under Targets 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-11-05.
Tam et al. (2026) studied this question.