Misbehaviour of XIST RNA in Breast Cancer Cells

Abstract

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.

High XIST and Low 53BP1 Expression Predict Poor Outcome after High-Dose Alkylating Chemotherapy in Patients with a BRCA1-like Breast Cancer

“…Abbreviation: lr, log rank. findings fit with the literature in which XIST expression, deregulation, and loss of the inactive X chromosome have been described in basal-like breast cancer over the last few years (16)(17)(18)(19)(20)(21). Unfortunately, this does not shed light on how XIST deregulation or the loss of an inactive X chromosome confers a resistance phenotype.…”

“…Thus, the patients in the clinical study did not represent the BRCA1 deficiency of the mouse model, because many patients were included without features of BRCA1 deficiency (12,14,15). Furthermore, because associations between dysfunction of BRCA1 and XIST have been frequently described, it may be that BRCA1 deficiency and low XIST expression identify a similar group of patients (12,(16)(17)(18)(19)(20)(21). For these two reasons, it is important to study XIST expression in the presence of BRCA1 deficiency, to recapitulate the findings in a brca1-deficient mouse model as closely as possible in the human situation (12).…”

The lesser known story of X chromosome reactivation

“…Some breast and ovarian cancer lines, like HCC and MCF7, do not stain positive for Xi, 38,39 prompting questions about their X-chromosome state. Because BRCA1 was shown to co-localize and co-immunoprecipitate with Xist, and BRCA1 -/-cells lack Xist foci, a role of BRCA1 in maintenance of Xi in female somatic cells is suggested.…”

“…Recent reports dispute the finding that BRCA1 interacts with Xist, as they find no co-localization between them. 39,41 Furthermore, MCF7 cell populations were found to consist of mostly Xistnegative cells, and this was suggested to be a result of loss of Xi and duplication of Xa. SNP analysis confirmed homogeneity of X alleles.…”

“…SNP analysis confirmed homogeneity of X alleles. 39 Thus, instability of chromosomes in cancer lines, rather than Xi conversion to Xa and its involvement of BRCA1, seems a likely occurrence as well. However, because various cancer and ovarian cells behave differently, neither explanation could be ruled out.…”