NF-κB at the Crossroads of Normal Mammary Gland Biology and the Pathogenesis and Prevention of BRCA1 -Mutated Breast Cancer

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 p...

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Published in:Cancer prevention research (Philadelphia, Pa.) Pa.), 2018-02, Vol.11 (2), p.69-80
Main Authors: Sau, Andrea, Cabrita, Miguel A, Pratt, M A Christine
Format: Article
Language:English
Subjects:
BRCA1 Protein - genetics
Breast - metabolism
Breast - pathology
Breast Neoplasms - genetics
Breast Neoplasms - metabolism
Breast Neoplasms - pathology
Cell Transformation, Neoplastic - genetics
Cell Transformation, Neoplastic - metabolism
Cell Transformation, Neoplastic - pathology
Female
Humans
Mutation
NF-kappa B - metabolism
Signal Transduction
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Summary: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 mutations ( ) as well as the luminal progenitor population in -deficient mouse mammary glands is abnormally amplified. Remarkably, mouse and human progenitor cells are able to form colonies in the absence of progesterone, demonstrating a hormone-independent proliferative capacity. Our research has demonstrated that proliferation in -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 -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 mutation carriers and ultimately reveal possibilities for nonsurgical prevention strategies. .
ISSN:1940-6207
1940-6215
DOI:10.1158/1940-6207.CAPR-17-0225