Misbehaviour of XIST RNA in breast cancer cells.
A role of X chromosome inactivation process in the development of breast cancer have been suggested. In particular, the relationship between the breast cancer predisposing gene BRCA1 and XIST, the main mediator of X chromosome inactivation, has been intensely investigated, but still remains controversial. We investigated this topic by assessing XIST behaviour in different groups of breast carcinomas and in a panel of breast cancer cell lines both BRCA1 mutant and wild type. In addition, we evaluated the occurrence of broader defects of heterochromatin in relation to BRCA1 status in breast cancer cells. We provide evidence that in breast cancer cells BRCA1 is involved in XIST regulation on the active X chromosome, but not in its localization as previously suggested, and that XIST can be unusually expressed by an active X and can decorate it. This indicates that the detection of XIST cloud in cancer cell is not synonymous of the presence of an inactive X chromosome. Moreover, we show that global heterochromatin defects observed in breast tumor cells are independent of BRCA1 status. Our observations sheds light on a possible previously uncharacterized mechanism of breast carcinogenesis mediated by XIST misbehaviour, particularly in BRCA1-related cancers. Moreover, the significant higher levels of XIST-RNA detected in BRCA1-associated respect to sporadic basal-like cancers, opens the possibility to use XIST expression as a marker to discriminate between the two groups of tumors.
Sirchia
Silvia M
SM
Department of Medicine, Surgery and Dentistry, Medical Genetics Unit, Università degli Studi di Milano, Milano, Italy. silvia.sirchia@unimi.it
Tabano
Silvia
S
Monti
Laura
L
Recalcati
Maria P
MP
Gariboldi
Manuela
M
Grati
Francesca R
FR
Porta
Giovanni
G
Finelli
Palma
P
Radice
Paolo
P
Miozzo
Monica
M
D019313:BRCA1 Protein / Q000235:genetics / Q000502:physiology; D001943:Breast Neoplasms / Q000503:physiopathology*; D002460:Cell Line; D045744:Cell Line, Tumor; D041321:Chromosomes, Human, X / Q000235:genetics; D019084:Fluorescent Antibody Technique, Indirect; D005838:Genotype; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D034622:RNA Interference; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated / Q000235:genetics / Q000502:physiology*; D020133:Reverse Transcriptase Polymerase Chain Reaction
D019313:BRCA1 Protein; D062085:RNA, Long Noncoding; D022661:RNA, Untranslated; C077885:XIST non-coding RNA