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Genetic characterization of breast cancer and implications for clinical management.

Geyer FC, Lopez-Garcia MA, Lambros MB, Reis-Filho JS - J. Cell. Mol. Med. (2009)

Bottom Line: In the last few years, high-throughput microarray-based molecular analysis has provided increasingly more coherent information about the genetic aberrations in breast cancer.New biomarkers and molecular techniques are slowly becoming part of the diagnostic and prognostic armamentarium available for pathologists and oncologists to tailor the therapy for breast cancer patients.In this review, we will focus on the contribution of breast cancer somatic genetics to our understanding of breast cancer biology and its impact on breast cancer patient management.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathology Laboratory, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

ABSTRACT
Breast cancer is a genetic disease caused by the accumulation of mutations in neoplastic cells. In the last few years, high-throughput microarray-based molecular analysis has provided increasingly more coherent information about the genetic aberrations in breast cancer. New biomarkers and molecular techniques are slowly becoming part of the diagnostic and prognostic armamentarium available for pathologists and oncologists to tailor the therapy for breast cancer patients. In this review, we will focus on the contribution of breast cancer somatic genetics to our understanding of breast cancer biology and its impact on breast cancer patient management.

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Conditional mouse models of basal-like and triple negative breast cancers. (A) Brca1 and Trp53 inactivation in different cellular compartments of the mouse mammary gland leads to the development of basal-like and triple negative breast cancers. In the Blg-Cre;Brca1F/F/Trp53+/− mouse model, Brca1 was inactivated in luminal epithelial cells of the mouse mammary gland and all cells harboured only one functional copy of Trp53. In the K14cre;Brca1F/F/Trp53F/F mouse model, Brca1 and Trp53 were inactivated in the basal/myoepithelial cells of the mouse mammary gland. Histopathological and immunohistochemical analysis of tumours developing in mouse models where Brca1 and Trp53 were inactivated in different lineages of the mouse mammary gland revealed that tumours had morphological and immunohistochemical features that recapitulated those of human basal-like breast cancers [8, 9] (i.e. a convergent phenotype driven by the type of genetic hits). (B) Representative scanning and medium power magnification micrographs of a tumour developing in Blg-Cre;Brca1F/F/Trp53+/− mouse model and in a patient with a pathogenic BRCA1 truncating germline mutation. Ck: cytokeratin; EGFR: epidermal growth factor receptor; IDC-NST: invasive ductal carcinoma of no special type; TN: triple negative.
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fig02: Conditional mouse models of basal-like and triple negative breast cancers. (A) Brca1 and Trp53 inactivation in different cellular compartments of the mouse mammary gland leads to the development of basal-like and triple negative breast cancers. In the Blg-Cre;Brca1F/F/Trp53+/− mouse model, Brca1 was inactivated in luminal epithelial cells of the mouse mammary gland and all cells harboured only one functional copy of Trp53. In the K14cre;Brca1F/F/Trp53F/F mouse model, Brca1 and Trp53 were inactivated in the basal/myoepithelial cells of the mouse mammary gland. Histopathological and immunohistochemical analysis of tumours developing in mouse models where Brca1 and Trp53 were inactivated in different lineages of the mouse mammary gland revealed that tumours had morphological and immunohistochemical features that recapitulated those of human basal-like breast cancers [8, 9] (i.e. a convergent phenotype driven by the type of genetic hits). (B) Representative scanning and medium power magnification micrographs of a tumour developing in Blg-Cre;Brca1F/F/Trp53+/− mouse model and in a patient with a pathogenic BRCA1 truncating germline mutation. Ck: cytokeratin; EGFR: epidermal growth factor receptor; IDC-NST: invasive ductal carcinoma of no special type; TN: triple negative.

Mentions: The study of germline genetic aberrations and breast cancer phenotypic diversity has also revealed another example of genotypic–phenotypic correlations in breast cancer. Tumours arising in BRCA1 germline mutation carriers display a rather specific constellation of morphological features and these features are strikingly similar to those described in basal-like breast cancers [28], including high histological grade, atypical medullary features, high proliferation indices, pushing borders and conspicuous lymphocytic infiltrate [98, 106, 107]. Over 75% of these cancers display a triple negative phenotype, express basal markers and display TP53 mutations [17, 108, 109]. In addition, tumours from BRCA1 mutation carriers cluster predominantly in the basal-like group by gene expression profiling [18, 110]. Taken together, there is evidence to suggest a strong genotypic–phenotypic correlation between BRCA1 and the basal-like phenotype [28, 41, 98, 111–113]. This genotypic–phenotypic correlation has been further confirmed by the development of two conditional mouse models, where Brca1 and Trp53 were inactivated either in the basal or luminal cells of the mouse mammary gland [8, 9]. These transgenic animals [8, 9] developed tumours whose histopathological, immunohistochemical and transcriptomic characteristics recapitulated the cardinal features of human basal-like breast cancers (Fig. 2).


Genetic characterization of breast cancer and implications for clinical management.

Geyer FC, Lopez-Garcia MA, Lambros MB, Reis-Filho JS - J. Cell. Mol. Med. (2009)

Conditional mouse models of basal-like and triple negative breast cancers. (A) Brca1 and Trp53 inactivation in different cellular compartments of the mouse mammary gland leads to the development of basal-like and triple negative breast cancers. In the Blg-Cre;Brca1F/F/Trp53+/− mouse model, Brca1 was inactivated in luminal epithelial cells of the mouse mammary gland and all cells harboured only one functional copy of Trp53. In the K14cre;Brca1F/F/Trp53F/F mouse model, Brca1 and Trp53 were inactivated in the basal/myoepithelial cells of the mouse mammary gland. Histopathological and immunohistochemical analysis of tumours developing in mouse models where Brca1 and Trp53 were inactivated in different lineages of the mouse mammary gland revealed that tumours had morphological and immunohistochemical features that recapitulated those of human basal-like breast cancers [8, 9] (i.e. a convergent phenotype driven by the type of genetic hits). (B) Representative scanning and medium power magnification micrographs of a tumour developing in Blg-Cre;Brca1F/F/Trp53+/− mouse model and in a patient with a pathogenic BRCA1 truncating germline mutation. Ck: cytokeratin; EGFR: epidermal growth factor receptor; IDC-NST: invasive ductal carcinoma of no special type; TN: triple negative.
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Related In: Results  -  Collection

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fig02: Conditional mouse models of basal-like and triple negative breast cancers. (A) Brca1 and Trp53 inactivation in different cellular compartments of the mouse mammary gland leads to the development of basal-like and triple negative breast cancers. In the Blg-Cre;Brca1F/F/Trp53+/− mouse model, Brca1 was inactivated in luminal epithelial cells of the mouse mammary gland and all cells harboured only one functional copy of Trp53. In the K14cre;Brca1F/F/Trp53F/F mouse model, Brca1 and Trp53 were inactivated in the basal/myoepithelial cells of the mouse mammary gland. Histopathological and immunohistochemical analysis of tumours developing in mouse models where Brca1 and Trp53 were inactivated in different lineages of the mouse mammary gland revealed that tumours had morphological and immunohistochemical features that recapitulated those of human basal-like breast cancers [8, 9] (i.e. a convergent phenotype driven by the type of genetic hits). (B) Representative scanning and medium power magnification micrographs of a tumour developing in Blg-Cre;Brca1F/F/Trp53+/− mouse model and in a patient with a pathogenic BRCA1 truncating germline mutation. Ck: cytokeratin; EGFR: epidermal growth factor receptor; IDC-NST: invasive ductal carcinoma of no special type; TN: triple negative.
Mentions: The study of germline genetic aberrations and breast cancer phenotypic diversity has also revealed another example of genotypic–phenotypic correlations in breast cancer. Tumours arising in BRCA1 germline mutation carriers display a rather specific constellation of morphological features and these features are strikingly similar to those described in basal-like breast cancers [28], including high histological grade, atypical medullary features, high proliferation indices, pushing borders and conspicuous lymphocytic infiltrate [98, 106, 107]. Over 75% of these cancers display a triple negative phenotype, express basal markers and display TP53 mutations [17, 108, 109]. In addition, tumours from BRCA1 mutation carriers cluster predominantly in the basal-like group by gene expression profiling [18, 110]. Taken together, there is evidence to suggest a strong genotypic–phenotypic correlation between BRCA1 and the basal-like phenotype [28, 41, 98, 111–113]. This genotypic–phenotypic correlation has been further confirmed by the development of two conditional mouse models, where Brca1 and Trp53 were inactivated either in the basal or luminal cells of the mouse mammary gland [8, 9]. These transgenic animals [8, 9] developed tumours whose histopathological, immunohistochemical and transcriptomic characteristics recapitulated the cardinal features of human basal-like breast cancers (Fig. 2).

Bottom Line: In the last few years, high-throughput microarray-based molecular analysis has provided increasingly more coherent information about the genetic aberrations in breast cancer.New biomarkers and molecular techniques are slowly becoming part of the diagnostic and prognostic armamentarium available for pathologists and oncologists to tailor the therapy for breast cancer patients.In this review, we will focus on the contribution of breast cancer somatic genetics to our understanding of breast cancer biology and its impact on breast cancer patient management.

View Article: PubMed Central - PubMed

Affiliation: Molecular Pathology Laboratory, The Breakthrough Breast Cancer Research Centre, Institute of Cancer Research, London, UK.

ABSTRACT
Breast cancer is a genetic disease caused by the accumulation of mutations in neoplastic cells. In the last few years, high-throughput microarray-based molecular analysis has provided increasingly more coherent information about the genetic aberrations in breast cancer. New biomarkers and molecular techniques are slowly becoming part of the diagnostic and prognostic armamentarium available for pathologists and oncologists to tailor the therapy for breast cancer patients. In this review, we will focus on the contribution of breast cancer somatic genetics to our understanding of breast cancer biology and its impact on breast cancer patient management.

Show MeSH
Related in: MedlinePlus