The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer

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Abstract

Abnormalities of chromosome 17 are important molecular genetic events in human breast cancers. Several famous oncogenes (HER2, TOP2A and TAU), tumor suppressor genes (p53, BRCA1 and HIC-1) or DNA double-strand break repair gene (RDM1) are located on chromosome 17. We searched the literature on HER2, TOP2A, TAU, RDM1, p53, BRCA1 and HIC-1 on the Pubmed database. The association of genes with chromosome 17, biological functions and potential significance are reviewed. In breast cancer, the polysomy 17 (three or more) is the predominant numerical aberration. HER2 amplification is widely utilized as molecular markers for trastuzumab target treatment. Amplified TOP2A, TAU and RDM1 genes are related to a significant response to anthracycline-based chemotherapy, taxane or cisplatin, respectively. In contrast, p53, BRCA1 and HIC-1 are important tumor suppressor genes related to breast carcinogenesis. This review focused on several crucial molecular markers residing on chromosome 17. The authors consider the somatic aberrations of chromosome 17 and associated genes in breast cancer.

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Most cited references 56

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A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

Y Miki, J. Swensen, D Shattuck-Eidens … (1994)

A strong candidate for the 17q-linked BRCA1 gene, which influences susceptibility to breast and ovarian cancer, has been identified by positional cloning methods. Probable predisposing mutations have been detected in five of eight kindreds presumed to segregate BRCA1 susceptibility alleles. The mutations include an 11-base pair deletion, a 1-base pair insertion, a stop codon, a missense substitution, and an inferred regulatory mutation. The BRCA1 gene is expressed in numerous tissues, including breast and ovary, and encodes a predicted protein of 1863 amino acids. This protein contains a zinc finger domain in its amino-terminal region, but is otherwise unrelated to previously described proteins. Identification of BRCA1 should facilitate early diagnosis of breast and ovarian cancer susceptibility in some individuals as well as a better understanding of breast cancer biology.

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Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.

Christian Tovar, James Rosinski, Zoran Filipovic … (2006)

The p53 tumor suppressor retains its wild-type conformation and transcriptional activity in half of all human tumors, and its activation may offer a therapeutic benefit. However, p53 function could be compromised by defective signaling in the p53 pathway. Using a small-molecule MDM2 antagonist, nutlin-3, to probe downstream p53 signaling we find that the cell-cycle arrest function of the p53 pathway is preserved in multiple tumor-derived cell lines expressing wild-type p53, but many have a reduced ability to undergo p53-dependent apoptosis. Gene array analysis revealed attenuated expression of multiple apoptosis-related genes. Cancer cells with mdm2 gene amplification were most sensitive to nutlin-3 in vitro and in vivo, suggesting that MDM2 overexpression may be the only abnormality in the p53 pathway of these cells. Nutlin-3 also showed good efficacy against tumors with normal MDM2 expression, suggesting that many of the patients with wild-type p53 tumors may benefit from antagonists of the p53-MDM2 interaction.

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Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer.

Johannes Peterse, Ben L. J. M. Mulder, Hanneke van Zoggel … (2007)

Women carrying germ-line mutations in BRCA1 are strongly predisposed to developing breast cancers with characteristic features also observed in sporadic basal-like breast cancers. They appear as high-grade tumors with high proliferation rates and pushing borders. On the molecular level, they are negative for hormone receptors and ERBB2, display frequent TP53 mutations, and express basal epithelial markers. To study the role of BRCA1 and P53 loss of function in breast cancer development, we generated conditional mouse models with tissue-specific mutation of Brca1 and/or p53 in basal epithelial cells. Somatic loss of both BRCA1 and p53 resulted in the rapid and efficient formation of highly proliferative, poorly differentiated, estrogen receptor-negative mammary carcinomas with pushing borders and increased expression of basal epithelial markers, reminiscent of human basal-like breast cancer. BRCA1- and p53-deficient mouse mammary tumors exhibit dramatic genomic instability, and their molecular signatures resemble those of human BRCA1-mutated breast cancers. Thus, these tumors display important hallmarks of hereditary breast cancers in BRCA1-mutation carriers.

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Author and article information

Journal

Journal ID (nlm-ta): Int J Mol Sci

Journal ID (publisher-id): ijms

Title: International Journal of Molecular Sciences

Publisher: Molecular Diversity Preservation International (MDPI)

ISSN (Electronic): 1422-0067

Publication date Collection: 2011

Publication date (Electronic): 5 September 2011

Volume: 12

Issue: 9

Pages: 5672-5683

Affiliations

[1 ]Department of Surgery, School of Medicine, The Ninth People’s Hospital of Shanghai Jiao Tong University, Shanghai 200011, China

[2 ]Department of Surgery, School of Medicine, Shanghai Ruijin Hospital of Shanghai Jiao Tong University, Shanghai 200025, China; E-Mail: yingyan3y@ 123456yahoo.com.cn

Author notes

[* ]Author to whom correspondence should be addressed; E-Mail: weizh1518@ 123456hotmail.com ; Tel.: +86-21-63138341; Fax: +86-21-63136856.

Article

Publisher ID: ijms-12-05672

DOI: 10.3390/ijms12095672

PMC ID: 3189742

PubMed ID: 22016618

SO-VID: 2f014028-cb9b-414c-b25c-40d3ad9b247d

License:

This article is an open-access article distributed under the terms and conditions of the Creative Commons Attribution license ( http://creativecommons.org/licenses/by/3.0/).

History

Date received : 13 July 2011

Date revision received : 16 August 2011

Date accepted : 31 August 2011

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The Important Molecular Markers on Chromosome 17 and Their Clinical Impact in Breast Cancer

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Most cited references 56

A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1.

Small-molecule MDM2 antagonists reveal aberrant p53 signaling in cancer: implications for therapy.

Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer.

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