J Med Assoc Thai 90 : 9— PubMed Google Scholar. Stordal B, Davey R A systematic review of genes involved in the inverse resistance relationship between cisplatin and paclitaxel chemotherapy: role of BRCA1. Curr Cancer Drug Targets 9 : — Mol Cancer 8 : 48— Cancer Res 68 : — J Clin Oncol 26 : — Nature : — Int J Gynecol Cancer 16 : — Nat Rev Cancer 4 : — Trends Mol Med 8 : — Cell : — Int J Cancer 24 : — Cancer Genet Cytogenet : — JAMA : — Cancer Sci 95 : — Download references.
Present address: Current address: Precision Therapeutics Inc. You can also search for this author in PubMed Google Scholar. Correspondence to T C Krivak. This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution-NonCommercial-Share Alike 3. From twelve months after its original publication, this work is licensed under the Creative Commons Attribution-NonCommercial-Share Alike 3.
Reprints and Permissions. Lesnock, J. BRCA1 expression and improved survival in ovarian cancer patients treated with intraperitoneal cisplatin and paclitaxel: a Gynecologic Oncology Group Study.
Br J Cancer , — Download citation. Received : 24 October Revised : 26 January Accepted : 27 January Published : 05 March Issue Date : 02 April Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. Scientific Reports Journal of Human Genetics British Journal of Cancer Prostate Cancer and Prostatic Diseases Advanced search.
Skip to main content Thank you for visiting nature. Download PDF. Subjects Chemotherapy Ovarian cancer Prognostic markers. This article has been updated. Results: Of the patients, tumours had aberrant expression, and had normal BRCA1 expression.
Statistical analysis Progression-free survival was calculated as time of randomisation to either disease recurrence or death from any cause before recurrence, and OS was calculated from randomisation to death from any cause. Figure 1. Full size image. Figure 2. Change history 02 April This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication.
View author publications. Gene name i Official gene symbol, which is typically a short form of the gene name, according to HGNC. Cancer-related genes Disease related genes Enzymes Plasma proteins Potential drug targets. Read more Low tissue specificity. Nuclear and cytoplasmic expression in a fraction of cells in several tissues. Medium consistency between antibody staining and RNA expression data. Expression Detection All organs. Protein expression score i Each bar represents the highest expression score found in a particular group of tissues.
Cerebral cortex Endothelial cells:. Olfactory region. Hippocampal formation. Hippocampus Glial cells:. Basal ganglia. Caudate Glial cells:. Pons and medulla. Cerebellum Cells in granular layer:. Corpus callosum. Spinal cord. Endocrine tissues. Thyroid gland. Thyroid gland Glandular cells:. Parathyroid gland.
Adrenal gland. Adrenal gland Glandular cells:. Pituitary gland. Nasopharynx Basal cells:. Bronchus Basal cells:.
Lung Alveolar cells:. Proximal digestive tract. Oral mucosa. Oral mucosa Squamous epithelial cells:. Salivary gland. Salivary gland Glandular cells:. Esophagus Squamous epithelial cells:. Gastrointestinal tract. Stomach 1 Stomach 2 Glandular cells:. Duodenum Glandular cells:.
Small intestine. Small intestine Glandular cells:. Colon Endothelial cells:. Rectum Glandular cells:. Liver Cholangiocytes:. Gallbladder Glandular cells:. Pancreas Exocrine glandular cells:.
Kidney Cells in glomeruli:. Urinary bladder. Urinary bladder Urothelial cells:. Male tissues. Ductus deferens. Testis Cells in seminiferous ducts:. Epididymis Glandular cells:. At the same time, decreased BRCA1 expression is an early event in the process of breast transformation, and progresses with the degree of malignancy. Given the known molecular functions of BRCA1, it is reasonable to assume that such decreases lead to a relaxation in genome surveillance. This relaxation would not be deleterious during normal development because BRCA1 levels are lowest when mammary epithelial cells are either quiescent or terminally differentiated.
However, changes in BRCA1 levels may also play an active role in regulating developmental processes, such as inducing postlactational regression. A number of transcription factors have been identified that regulate BRCA1 expression. These factors presumably lie at the end of a variety of signalling pathways that are initiated by molecular regulators of developmental change in the mammary gland. Importantly, many of the signals initiated by these regulators have themselves been implicated in mammary oncogenesis.
Thus, we propose that mutations in the transcription factors themselves or alterations to the developmentally regulated signalling pathways that modulate their activity contribute to the inappropriate repression of BRCA1 expression. Obviously, these two possibilities are not mutually exclusive and could be overlapping.
Cross-talk occurs between basement membrane-mediated signalling, prolactin signalling and morphogenic erbB receptor signalling during development [ 67 , 66 , 71 , 72 ].
This would ensure that in quiescent cells the ECM signal prevents BRCA1 induction, but during growth this blockade is lifted, and prolactin and erbB signals, which are proliferative outside the context of morphogenesis and lactational differentiation, result in BRCA1 induction. Tumour cell survival presumably requires abrogation of this BRCA1 induction. There are observational and experimental data that indirectly support this tentative hypothesis.
First, in sporadic tumours BRCA1 levels are most affected after progression from ductal carcinoma in situ [ 12 ], a time when the basement membrane is undergoing chronic remodelling. Second, mammary-specific expression of an activated metalloprotease that remodels the basement membrane [ 73 , 74 ] causes a morphogenic and stochastic tumour formation in transgenic mice that is reminiscent of the phenotype observed in the targeted BRCA1 knockout [ 8 ].
Third, a developmentally inappropriate integrin signal switching that contributes to breast tumour progression causes erbB signalling to become oncogenic [ 75 , 76 ]. Fourth, oncogenic erbB signalling and BRCA1 expression are inversely correlated in tumour cells [ 18 ]. Finally, forced expression of ID1, which is closely related to the BRCA1 repressor ID4, causes mammary epithelial cells to proliferate rather than differentiate when they are exposed to a basement membrane ECM [ 77 , 78 ].
Transcription factors that regulate the BRCA1 promoter directly modulate the production of this tumour suppressor, and thus their loss or gain of function will have the same functional consequences as inactivation of BRCA1 itself. This raises the question of whether these factors act as sporadic breast cancer genes. Optimal BRCA1 expression requires the concerted action of a number of transcription factors, so that inactivation of any one protein will affect BRCA1 levels.
Given a random distribution of sporadic mutations in the genome, it may be more likely that one of a number of different transcription factor genes would be a target, rather than the BRCA1 gene itself.
In addition, loss of activity from a single allele of a transcription factor gene may be sufficient to decrease BRCA1 expression significantly, with functional consequences.
This may explain why sporadic mutations in BRCA1 have not been observed, because these may be rarer events than transcription factor gene mutations. Furthermore, as discussed above, loss of transcriptional regulators of BRCA1 may not require actual mutational events. Disruption of the signalling pathways that regulate BRCA1 expression could have long-term consequences for the associated transcriptional regulators, which persist through subsequent progression events.
In some cases, BRCA1 transcription is reduced sufficiently for methylation of the promoter to occur, creating a self-sustaining repressed state. It may be possible to restore BRCA1 expression in tumours. This could be achieved by the use of demethylating agents such as deazacytadine, inducing alternative pathways where mutations have blocked other factors, or restoring developmental signals that have been co-opted. Induction of BRCA1 expression has been shown to induce apoptosis or reduce growth in tumour cells [ 12 ], and offers an alternative therapeutic approach that may be tumour specific.
National Center for Biotechnology Information , U. Journal List Breast Cancer Res v. Breast Cancer Res. Published online Nov Author information Article notes Copyright and License information Disclaimer. Corresponding author. Christopher R Mueller: ac.
This article has been cited by other articles in PMC. Abstract Germ-line mutations in the BRCA1 tumour suppressor gene contribute to familial breast tumour formation, but there is no evidence for direct mutation of the BRCA1 gene in the sporadic form of the disease. Keywords: BRCA1 , breast cancer, development, transcription, sporadic. Loss of heterozygosity and methylation of the BRCA1 promoter There are several potential mechanisms that could lead to a permanent decrease in BRCA1 levels in sporadic breast tumours.
Open in a separate window. Figure 1. Figure 2. Figure 3. Developmental regulation of BRCA1 expression in mammary gland The developmental regulation of BRCA1 expression has been most extensively studied in the mouse [ 54 - 58 ]. Figure 4. Molecular regulators of mammary development Mammary development is directed by at least three classes of molecular regulators. Conclusion BRCA1 expression is clearly modulated by developmental regulators in the normal mammary gland.
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Conditional mutation of Brca1 in mammary epithelial cells results in blunted ductal morphogenesis and tumour formation. BRCA1 mutations in primary breast and ovarian carcinomas. Identification of a possible somatic BRCA1 mutation affecting translation efficiency in an early-onset sporadic breast cancer patient. J Natl Cancer Inst. A sporadic breast tumor with a somatically acquired complex genomic rearrangement in BRCA1. Genes Chromosomes Cancer. Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression.
An important role for BRCA1 in breast cancer progression is indicated by its loss in a large proportion of non-familial breast cancers. Int J Cancer. Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype. Cancer Genet Cytogenet. Immunolocalization of BRCA1 protein in normal breast tissue and sporadic invasive ductal carcinomas: a correlation with other biological parameters.
BRCA1 expression levels predict distant metastasis of sporadic breast cancers. Clin Cancer Res. Regulation of BRCA1 by protein degradation. Int J Oncol. Preferential allelic expression can lead to reduced expression of BRCA1 in sporadic breast cancers.
Promoter-region hypermethylation and gene silencing in human cancer. Curr Top Microbiol Immunol. Methylation of the BRCA1 gene in sporadic breast cancer. Cancer Res.
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