NF-κB at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1-Mutated Breast Cancer.
Cancer Prev Res (Phila)
; 11(2): 69-80, 2018 02.
Article
en En
| MEDLINE
| ID: mdl-29101208
ABSTRACT
Recent studies have shown that progesterone receptor (PR)-expressing cells respond to progesterone in part through the induction of the receptor activator of NF-κB ligand (RANKL), which acts in a paracrine manner to induce expansion of a RANK-expressing luminal progenitor cell population. The RANK+ population in human breast tissue from carriers of BRCA1 mutations (BRCA1mut/+) as well as the luminal progenitor population in Brca1-deficient mouse mammary glands is abnormally amplified. Remarkably, mouse Brca1+/- and human BRCA1mut/+ progenitor cells are able to form colonies in vitro in the absence of progesterone, demonstrating a hormone-independent proliferative capacity. Our research has demonstrated that proliferation in BRCA1-deficient cells results in a DNA damage response (DDR) that activates a persistent NF-κB signal, which supplants progesterone/RANKL signaling for an extended time period. Thus, the transcriptional targets normally activated by RANKL that promote a proliferative response in luminal progenitors can contribute to the susceptibility of mammary epithelial cells to BRCA1-mutated breast cancers as a consequence of DDR-induced NF-κB. Together, these latest findings mark substantial progress in uncovering the mechanisms driving high rates of breast tumorigenesis in BRCA1 mutation carriers and ultimately reveal possibilities for nonsurgical prevention strategies. Cancer Prev Res; 11(2); 69-80. ©2017 AACR.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Mama
/
Neoplasias de la Mama
/
Transformación Celular Neoplásica
/
FN-kappa B
/
Proteína BRCA1
/
Mutación
Tipo de estudio:
Etiology_studies
Límite:
Female
/
Humans
Idioma:
En
Revista:
Cancer Prev Res (Phila)
Asunto de la revista:
NEOPLASIAS
Año:
2018
Tipo del documento:
Article
País de afiliación:
Canadá