Defining and Modulating ‘BRCAness’

Byrum, Andrea K.; Vindigni, Alessandro; Mosammaparast, Nima

doi:10.1016/j.tcb.2019.06.005

Cited by 122 publications

(118 citation statements)

References 84 publications

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“…Another possibility for stratifying patients who will benefit from a combination of PARP and ATR inhibitors would be to use a surrogate marker of ATM functionality, either through the use of phosphospecific antibodies to ATM itself or its downstream targets or an RNA signature specific to loss of ATM functionality. Indeed, the search for identifying tumours which exhibit "BRCAness" or HRR deficiency is an area of active investigation [27,86]. Answers to these questions and more may become apparent over the next few years as PARP inhibitor therapy is tested in more patients with defects in DNA damage response genes.…”

Section: Atm Mutation Versus Loss Of Function: Identifying Patients Wmentioning

confidence: 99%

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Jette

Kumar

Radhamani

et al. 2020

Cancers

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Poly-ADP ribose polymerase (PARP) inhibitors are currently used in the treatment of several cancers carrying mutations in the breast and ovarian cancer susceptibility genes BRCA1 and BRCA2, with many more potential applications under study and in clinical trials. Here, we discuss the potential for extending PARP inhibitor therapies to tumours with deficiencies in the DNA damage-activated protein kinase, Ataxia-Telangiectasia Mutated (ATM). We highlight our recent findings that PARP inhibition alone is cytostatic but not cytotoxic in ATM-deficient cancer cells and that the combination of a PARP inhibitor with an ATR (ATM, Rad3-related) inhibitor is required to induce cell death.

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Section: Atm Mutation Versus Loss Of Function: Identifying Patients Wmentioning

confidence: 99%

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Jette

Kumar

Radhamani

et al. 2020

Cancers

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“…38 PARP inhibitors are approved for the treatment of breast cancer patients with inherited cancer-associated BRCA1/2 mutations, and ongoing clinical trials are evaluating the efficacy of PARP inhibitors for the treatment of sporadic, triple-negative breast cancers that share similarities, or "BRCA-ness," with inherited BRCA1/2mutant breast cancers. 39,40 Therefore, our newly characterized Bard1-deficient, orthotopic metastasis model can be used to accelerate the evaluation of PARP inhibitor efficacy in metastatic breast cancers harboring sensitizing BRCA1/2 pathway mutations. Interestingly, PARP activity may also promote cachexia.…”

Section: Discussionmentioning

confidence: 99%

Aberrant Zip14 expression in muscle is associated with cachexia in a Bard1‐deficient mouse model of breast cancer metastasis

Shakri

Zhong

et al. 2020

Cancer Medicine

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Nearly 80% of advanced cancer patients are afflicted with cachexia, a debilitating syndrome characterized by extensive loss of muscle mass and function. Cachectic cancer patients have a reduced tolerance to antineoplastic therapies and often succumb to premature death from the wasting of respiratory and cardiac muscles. Since there are no available treatments for cachexia, it is imperative to understand the mechanisms that drive cachexia in order to devise effective strategies to treat it. Although 25% of metastatic breast cancer patients develop symptoms of muscle wasting, mechanistic studies of breast cancer cachexia have been hampered by a lack of experimental models. Using tumor cells deficient for BARD1, a subunit of the BRCA1/BARD1 tumor suppressor complex, we have developed a new orthotopic model of triple‐negative breast cancer that spontaneously metastasizes to the lung and leads to systemic muscle deterioration. We show that expression of the metal‐ion transporter, Zip14, is markedly upregulated in cachectic muscles from these mice and is associated with elevated intramuscular zinc and iron levels. Aberrant Zip14 expression and altered metal‐ion homeostasis could therefore represent an underlying mechanism of cachexia development in human patients with triple‐negative breast cancer. Our study provides a unique model for studying breast cancer cachexia and identifies a potential therapeutic target for its treatment.

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“…As a common function between BRCA1 and BRCA2, HR is an essential DNA repair system that enables the errorfree recovery of double strand breaks (DSBs) (17). DSBs are the most severe DNA damage, the accumulation of which results in genetic translocation and cell death (18). In the condition of homologous recombination deficiency (HRD) by BRCA dysfunction, restoration of DSBs depends on an errorprone repair machinery, known as non-homologous end joining (NHEJ).…”

Section: Functional Similarities and Differences Between Brca1 And Brca2mentioning

confidence: 99%

Molecular Trajectory of BRCA1 and BRCA2 Mutations

et al. 2020

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Every cancer carries genomic mutations. Although almost all these mutations arise after fertilization, a minimal count of cancer predisposition mutations are already present at the time of genesis of germ cells. Of the cancer predisposition genes identified to date, BRCA1 and BRCA2 have been determined to be associated with hereditary breast and ovarian cancer syndrome. Such cancer predisposition genes have recently been attracting attention owing to the emergence of molecular genetics, thus, affecting the strategy of cancer prevention, diagnostics, and therapeutics. In this review, we summarize the molecular significance of these two BRCA genes. First, we provide a brief history of BRCA1 and BRCA2, including their identification as cancer predisposition genes and recognition as members in the Fanconi anemia pathway. Next, we describe the molecular function and interaction of BRCA proteins, and thereafter, describe the patterns of BRCA dysfunction. Subsequently, we present emerging evidence on mutational signatures to determine the effects of BRCA disorders on the mutational process in cancer cells. Currently, BRCA genes serve as principal targets for clinical molecular oncology, be they germline or sporadic mutations. Moreover, comprehensive cancer genome analyses enable us to not only recognize the current status of the known cancer driver gene mutations but also divulge the past mutational processes and predict the future biological behavior of cancer through the molecular trajectory of genomic alterations.

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Defining and Modulating ‘BRCAness’

Cited by 122 publications

References 84 publications

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

ATM-Deficient Cancers Provide New Opportunities for Precision Oncology

Aberrant Zip14 expression in muscle is associated with cachexia in a Bard1‐deficient mouse model of breast cancer metastasis

Molecular Trajectory of BRCA1 and BRCA2 Mutations

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