Loss of the receptors ER, PR and HER2 promotes USP15-dependent stabilization of PARP1 in triple-negative breast cancer
Menée à l'aide de lignées cellulaires, d'échantillons tumoraux et de modèles murins de cancer mammaire triple négatif, cette étude met en évidence un mécanisme par lequel la perte de l'expression des récepteurs ER, PR et HER2 favorise la stabilisation de la polymérase PARP1 en agissant sur l'expression ou l'activité déubiquitinase de la peptidase USP15 ou encore sur l'interaction de cette dernière avec PARP1
Poly(ADP-ribose) polymerase 1 (PARP1) is essential for the progression of several types of cancers. However, whether and how PARP1 is stabilized to promote genomic stability in triple-negative breast cancer (TNBC) remains unknown. Here, we demonstrated that the deubiquitinase USP15 interacts with and deubiquitinates PARP1 to promote its stability, thereby stimulating DNA repair, genomic stability and TNBC cell proliferation. Two PARP1 mutations found in individuals with breast cancer (E90K and S104R) enhanced the PARP1–USP15 interaction and suppressed PARP1 ubiquitination, thereby elevating the protein level of PARP1. Importantly, we found that estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor 2 (HER2) inhibited USP15-mediated PARP1 stabilization through different mechanisms. ER bound to the USP15 promoter to suppress its expression, PR suppressed the deubiquitinase activity of USP15, and HER2 abrogated the PARP1–USP15 interaction. The specific absence of these three receptors in TNBC results in high PARP1 levels, leading to increases in base excision repair and female TNBC cell survival.