Details

Autor(en) / Beteiligte

• He, Zhengcheng
• Kannan, Nagarajan
• Nemirovsky, Oksana
• Chen, Helen
• Connell, Marisa
• Taylor, Brian
• Jiang, Jihong
• Pilarski, Linda M
• Fleisch, Markus C
• Niederacher, Dieter
• Pujana, Miguel Angel
• Eaves, Connie J
• Maxwell, Christopher A

Titel

BRCA1 controls the cell division axis and governs ploidy and phenotype in human mammary cells

Ist Teil von

• Oncotarget, 2017-05, Vol.8 (20), p.32461-32475

Ort / Verlag

United States: Impact Journals LLC

Erscheinungsjahr

2017

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• BRCA1 deficiency may perturb the differentiation hierarchy present in the normal mammary gland and is associated with the genesis of breast cancers that are genomically unstable and typically display a basal-like transcriptome. Oriented cell division is a mechanism known to regulate cell fates and to restrict tumor formation. We now show that the cell division axis is altered following shRNA-mediated BRCA1 depletion in immortalized but non-tumorigenic, or freshly isolated normal human mammary cells with graded consequences in progeny cells that include aneuploidy, perturbation of cell polarity in spheroid cultures, and a selective loss of cells with luminal features. BRCA1 depletion stabilizes HMMR abundance and disrupts cortical asymmetry of NUMA-dynein complexes in dividing cells such that polarity cues provided by cell-matrix adhesions were not able to orient division. We also show that immortalized mammary cells carrying a mutant BRCA1 allele (BRCA1 185delAG/+) reproduce many of these effects but in this model, oriented divisions were maintained through cues provided by CDH1+ cell-cell junctions. These findings reveal a previously unknown effect of BRCA1 suppression on mechanisms that regulate the cell division axis in proliferating, non-transformed human mammary epithelial cells and consequent downstream effects on the mitotic integrity and phenotype control of their progeny.