J Breast Cancer.  2019 Mar;22(1):1-14. 10.4048/jbc.2019.22.e6.

BRCA1 and Breast Cancer: a Review of the Underlying Mechanisms Resulting in the Tissue-Specific Tumorigenesis in Mutation Carriers

• Semmler L
• Reiter-Brennan C
• Klein A

• KMID: 2441847
• DOI: http://doi.org/10.4048/jbc.2019.22.e6

Abstract

Since the first cloning of BRCA1 in 1994, many of its cellular interactions have been elucidated. However, its highly specific role in tumorigenesis in the breast tissue"”carriers of BRCA1 mutations are predisposed to life-time risks of up to 80%"”relative to many other tissues that remain unaffected, has not yet been fully enlightened. In this article, we have applied a universal model of tissue-specificity of cancer genes to BRCA1 and present a systematic review of proposed concepts classified into 4 categories. Firstly, tissue-specific differences in levels of BRCA1 expression and secondly differences in expression of proteins with redundant functions are outlined. Thirdly, cell-type specific interactions of BRCA1 are presented: its regulation of aromatase, its interaction with Progesterone- and receptor activator of nuclear factor-κB ligand-signaling that controls proliferation of luminal progenitor cells, and its influence on cell differentiation via modulation of the key regulators jagged 1-NOTCH and snail family transcriptional repressor 2. Fourthly, factors specific to the cell-type as well as the environment of the breast tissue are elucidated: distinct frequency of losses of heterozygosity, interaction with X inactivation specific transcript RNA, estrogen-dependent induction of genotoxic metabolites and nuclear factor (erythroid-derived 2)-like 2, and regulation of sirtuin 1. In conclusion, the impact of these concepts on the formation of hormone-sensitive and -insensitive breast tumors is outlined.

Keyword

BRCA1 protein; Genes, BRCA1; Breast neoplasms; Haploinsufficiency; Organ specificity

MeSH Terms

Aromatase
BRCA1 Protein
Breast Neoplasms*
Breast*
Carcinogenesis*
Cell Differentiation
Clone Cells
Cloning, Organism
Genes, BRCA1
Genes, Neoplasm
Haploinsufficiency
Humans
Organ Specificity
Phenobarbital
RNA
Sirtuin 1
Snails
Stem Cells
X Chromosome Inactivation
Aromatase
BRCA1 Protein
Phenobarbital
RNA
Sirtuin 1

Figure

• 

  Figure 1 Domains of and selected proteins that interact with BRCA1.BARD1 = BRCA1-associated RING domain protein 1; PALB2 = partner and localizer of BRCA2; CTIP = C-terminal binding protein interacting protein; ABRAXAS = BRCA1 A complex subunit; BACH1 = BTB domain and CNC homolog 1; BRCT = BRCA1 C-terminus.

• 

  Figure 2 The interaction of different concepts for tissue-specific tumorigenesis in BRCA1 mutation carriers.All arrows behind proteins or processes indicate their change of activity in comparison to non-mutated individuals (aromatase ↑ indicates that its activity in mutation carriers is increased). Arrows between proteins or processes indicate whether the interaction increases or decreases the activity of the affected participant (BRCA1 ⟞ aromatase indicates that BRCA1 decreases aromatase's activity; consequently BRCA ↓ ⟞ aromatase ↑ indicates that 1) BRCA1 is decreased in mutation carriers, 2) that it physiologically decreases aromatases activity, and 3) that aromatase's activity is subsequently increased in mutation carriers). Not all concepts are illustrated. For detailed information see text.ES = estrogen; ER = estrogen receptor; PO = progesterone; PR = progesterone receptor; NF-κB = nuclear factor-κB; NRF2 = nuclear factor (erythroid-derived 2)-like 2; RANKL = receptor activator of nuclear factor-κB ligand; JAG1 = jagged 1; CYP1A1 = cytochrome P450 1A1; SIRT1 = sirtuin 1; SNAI2 = snail family transcriptional repressor 2.

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