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

BACKGROUND

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.

AIMS: This study aimed to elucidate the relationship between BRCA2 deficiency and ER signaling using integrated clinical and in vitro analyses.

METHODS AND

RESULTS

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.

CONCLUSION

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.