Altered Estrogen Receptor Signaling Pathway in BRCA2-Deficient Estrogen Receptor-Positive/HER2-Negative Breast Cancer.

Hereditary breast cancer accounts for approximately 10% of all breast cancer cases, with germline BRCA2 pathogenic variants (PVs) being the most prevalent genetic alteration. BRCA2 PVs predominantly lead to estrogen receptor (ER)-positive/HER2-negative breast cancers, which exhibit more aggressive phenotypes compared to sporadic cases. However, the specific effect of BRCA2 deficiency on ER signaling remains poorly understood. This study aimed to elucidate the relationship between BRCA2 deficiency and ER signaling using integrated clinical and in vitro analyses. Immunohistochemical analyses were performed on ER-positive/HER2-negative breast tumors from BRCA2 PV carriers (n = 8) and BRCA2 wild-type patients (n = 59). Furthermore, two BRCA2-deficient ER-positive/HER2-negative MCF7 cell lines were generated using CRISPR-Cas9 with two distinct guide RNAs targeting BRCA2, followed by Western blotting and functional assays. Immunohistochemical analyses demonstrated significantly lower levels of phosphorylated (p)-ER Ser167, p-AKT Ser473, and RB1 in BRCA2 PV carriers compared to patients with BRCA2 wild-type (p = 0.002, 0.018, and 0.037, respectively). Western blotting confirmed reduced p-ER Ser167, p-AKT Ser473, and RB1 levels in BRCA2-deficient cells relative to parental MCF7 cells. Decreased ER and AKT phosphorylation was not associated with consistent changes in the expression levels of downstream estrogen-responsive genes or proteins. Functional assays revealed that BRCA2 deficiency significantly increased sensitivity to the poly (ADP-ribose) polymerase inhibitor olaparib, whereas tamoxifen sensitivity remained unchanged. This study presents the first detailed characterization of ER signaling alterations in ER-positive/HER2-negative breast cancers with germline BRCA2 PVs, offering insights for the development of targeted therapeutic strategies for this patient population.