Deregulated estrogen receptor signaling and DNA damage response in breast tumorigenesis

Rajan, A. R.; Nadhan, Revathy; Latha, Neetha Rajan; Krishnan, Neethu; Warrier, Arathy; Srinivas, Priya

doi:10.1016/j.bbcan.2020.188482

Cited by 19 publications

(24 citation statements)

References 99 publications

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“…The effect by which hormonal contraceptives are thought to influence breast cancer risk could be due to direct stimulatory action on breast tissue, for instance, via cross regulatory signalling networks between the estrogen receptor (ER) α and BRCA1, 27 or indirectly via delayed childbirth and lower parity. Recently a meta-analysis pointed out that HC-induced risk was tied to breast cancer receptor status, where increased risks were noted for women with ER negative and triplet-negative breast cancer.…”

Section: Discussionmentioning

confidence: 99%

Hormonal contraception and risk of breast cancer and breast cancer in situ among Swedish women 15–34 years of age: A nationwide register-based study

Hultstrand

Gemzell‐Danielsson²,

Kallner³

et al. 2022

The Lancet Regional Health - Europe

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Section: Discussionmentioning

confidence: 99%

Hormonal contraception and risk of breast cancer and breast cancer in situ among Swedish women 15–34 years of age: A nationwide register-based study

Hultstrand

Gemzell‐Danielsson²,

Kallner³

et al. 2022

The Lancet Regional Health - Europe

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“…In the case of the real breast cancer profiles analysed, both moderated t-test and Hy-test reveal that DE genes are enriched in functions involved in tissue development and cell proliferation, as expected 24 . While the t-test approach focuses on signal transduction 25 – 27 , the Hy-test highlights a central role in regulating the cell cycle in breast cancer, as strongly supported by recent literature 28 , 29 .…”

Section: Discussionmentioning

confidence: 94%

A multivariate statistical test for differential expression analysis

Tumminello

Bertolazzi

Sottile

et al. 2022

Sci Rep

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Statistical tests of differential expression usually suffer from two problems. Firstly, their statistical power is often limited when applied to small and skewed data sets. Secondly, gene expression data are usually discretized by applying arbitrary criteria to limit the number of false positives. In this work, a new statistical test obtained from a convolution of multivariate hypergeometric distributions, the Hy-test, is proposed to address these issues. Hy-test has been carried out on transcriptomic data from breast and kidney cancer tissues, and it has been compared with other differential expression analysis methods. Hy-test allows implicit discretization of the expression profiles and is more selective in retrieving both differential expressed genes and terms of Gene Ontology. Hy-test can be adopted together with other tests to retrieve information that would remain hidden otherwise, e.g., terms of (1) cell cycle deregulation for breast cancer and (2) “programmed cell death” for kidney cancer.

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“…To analyse the protein expression, immunoblotting was carried out for different proteins in the whole cell lysates of cell lines as described earlier [27]. The details of Antibodies used in this study are given in Table S3.…”

Section: Methodsmentioning

confidence: 99%

BRCA1 Hypermethylation In Sporadic Breast Cancers: Discovering A Novel Pathway To Tumorigenesis Via Coordinate NBR2 Deregulation And TNBC Transformation

Patra

Varghese

Jaikumar

et al. 2022

Preprint

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Women with a family history of mutations in the Breast cancer susceptibility gene, BRCA1 will have an increased risk of developing breast neoplasms. However, majority of the breast cancers are sporadic where BRCA1 mutations are very rare. Instead, 5-65% of sporadic cases manifest BRCA1 promoter hypermethylation and 30-40% of such cases are develop into Triple Negative Breast Cancers. Even then, the molecular mechanism of BRCA1 hypermethylation mediated breast tumorigenesis has remained an enigma till date. Here, we present a novel tumorigenesis pathway for breast cancers that engenders from BRCA1 hypermethylation by using a modified version of CRISPR technology.We report that induction of site-specific methylation on BRCA1 promoter α effectuates a downregulation in BRCA1 expression via alteration in the balance between its alternate transcripts β and α. Induced BRCA1 hypermethylation is also responsible for the attenuation of a long noncoding RNA, NBR2 (Neighbour of BRCA1 gene 2), which is transcribed through the bidirectional BRCA1 promoter α in the reverse direction. Downregulation of NBR2 activates a feedback loop by leading to further downregulation of BRCA1 which is more evident under glucose starvation conditions and is associated with an impaired DNA damage repair pathway. Further, BRCA1 hypermethylation also results in significant overexpression of β-hCG (human chorionic gonadotrophin), which was found to be associated with highly aggressive and drug-resistant forms of BRCA1 mutated breast cancers invitro & in vivo in our previous study. Finally, we report a variation in the hormone receptor levels as the tumor progresses which suggests how BRCA1 deficient cells modulate their expression of ER-α and ER-β to promote their proliferation in early stages of tumor development and at later stages, transform to a basal tumor subtype by shedding down the expression of ER-α & PR.GRAPHICAL ABSTRACT

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Deregulated estrogen receptor signaling and DNA damage response in breast tumorigenesis

Cited by 19 publications

References 99 publications

Hormonal contraception and risk of breast cancer and breast cancer in situ among Swedish women 15–34 years of age: A nationwide register-based study

Hormonal contraception and risk of breast cancer and breast cancer in situ among Swedish women 15–34 years of age: A nationwide register-based study

A multivariate statistical test for differential expression analysis

BRCA1 Hypermethylation In Sporadic Breast Cancers: Discovering A Novel Pathway To Tumorigenesis Via Coordinate NBR2 Deregulation And TNBC Transformation

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