Negative Regulation of BRCA1 Gene Expression by HMGA1 Proteins Accounts for the Reduced BRCA1 Protein Levels in Sporadic Breast Carcinoma

Overview

Journal Mol Cell Biol

Specialty Cell Biology

Date 2003 Mar 18

PMID 12640109

Citations 49

Authors

Gustavo Baldassarre

Sabrina Battista

Barbara Belletti

Sanjay Thakur

Francesca Pentimalli

Francesco Trapasso

Monica Fedele

Giovanna Pierantoni

Carlo M Croce

Alfredo Fusco

Affiliations

Soon will be listed here.

Abstract

A drastic reduction in BRCA1 gene expression is a characteristic feature of aggressive sporadic breast carcinoma. However, the mechanisms underlying BRCA1 downregulation in breast cancer are not well understood. Here we report that both in vitro and in vivo HMGA1b protein binds to and inhibits the activity of both human and mouse BRCA1 promoters. Consistently, murine embryonic stem (ES) cells with the Hmga1 gene deleted display higher Brca1 mRNA and protein levels than do wild-type ES cells. Stable transfection of MCF-7 cells with the HMGA1b cDNA results in a decrease of BRCA1 gene expression and in a lack of BRCA1 induction after estrogen treatment. Finally, we found an inverse correlation between HMGA1 and BRCA1 mRNA and protein expression in human mammary carcinoma cell lines and tissues. These data indicate that HMGA1 proteins are involved in transcriptional regulation of the BRCA1 gene, and their overexpression may have a role in BRCA1 downregulation observed in aggressive mammary carcinomas.

Citing Articles

The deubiquitinating enzyme USP4 regulates BRCA1 stability and function.

Guo X, Ma Y, Zhang T, Liu R, Chang F, Yan X NPJ Breast Cancer. 2024; 10(1):35.

PMID: 38734703 PMC: 11088691. DOI: 10.1038/s41523-024-00641-7.

HMGA2 directly mediates chromatin condensation in association with neuronal fate regulation.

Kuwayama N, Kujirai T, Kishi Y, Hirano R, Echigoya K, Fang L Nat Commun. 2023; 14(1):6420.

PMID: 37828010 PMC: 10570362. DOI: 10.1038/s41467-023-42094-9.

Unveiling the vulnerabilities of synthetic lethality in triple-negative breast cancer.

Chatterjee P, Karn R, Isaac A, Ray S Clin Transl Oncol. 2023; 25(11):3057-3072.

PMID: 37079210 DOI: 10.1007/s12094-023-03191-9.

Chromatin regulators-related lncRNA signature predicting the prognosis of kidney renal clear cell carcinoma and its relationship with immune microenvironment: A study based on bioinformatics and experimental validation.

Zhang X, Qin X, Yu T, Wang K, Chen Y, Xing Q Front Genet. 2022; 13:974726.

PMID: 36338996 PMC: 9630733. DOI: 10.3389/fgene.2022.974726.

HMGA Proteins in Hematological Malignancies.

Minervini A, Coccaro N, Anelli L, Zagaria A, Specchia G, Albano F Cancers (Basel). 2020; 12(6).

PMID: 32503270 PMC: 7353061. DOI: 10.3390/cancers12061456.

References

Reeves R, Beckerbauer L . HMGI/Y proteins: flexible regulators of transcription and chromatin structure. Biochim Biophys Acta. 2001; 1519(1-2):13-29. DOI: 10.1016/s0167-4781(01)00215-9. View

Fan S, Wang J, Yuan R, Ma Y, Meng Q, Erdos M . BRCA1 inhibition of estrogen receptor signaling in transfected cells. Science. 1999; 284(5418):1354-6. DOI: 10.1126/science.284.5418.1354. View

Hartman A, Ford J . BRCA1 induces DNA damage recognition factors and enhances nucleotide excision repair. Nat Genet. 2002; 32(1):180-4. DOI: 10.1038/ng953. View

Soriano P, Montgomery C, Geske R, Bradley A . Targeted disruption of the c-src proto-oncogene leads to osteopetrosis in mice. Cell. 1991; 64(4):693-702. DOI: 10.1016/0092-8674(91)90499-o. View

Braunstein M, Rose A, Holmes S, Allis C, Broach J . Transcriptional silencing in yeast is associated with reduced nucleosome acetylation. Genes Dev. 1993; 7(4):592-604. DOI: 10.1101/gad.7.4.592. View

Ram T, Reeves R, Hosick H . Elevated high mobility group-I(Y) gene expression is associated with progressive transformation of mouse mammary epithelial cells. Cancer Res. 1993; 53(11):2655-60. View

Tamimi Y, van der Poel H, Denyn M, Umbas R, Karthaus H, Debruyne F . Increased expression of high mobility group protein I(Y) in high grade prostatic cancer determined by in situ hybridization. Cancer Res. 1993; 53(22):5512-6. View

Futreal P, Liu Q, Cochran C, Harshman K, Tavtigian S, Bennett L . BRCA1 mutations in primary breast and ovarian carcinomas. Science. 1994; 266(5182):120-2. DOI: 10.1126/science.7939630. View

Miki Y, Swensen J, Futreal P, Harshman K, Tavtigian S, Liu Q . A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science. 1994; 266(5182):66-71. DOI: 10.1126/science.7545954. View

10.

Berlingieri M, Manfioletti G, Santoro M, Bandiera A, Visconti R, Giancotti V . Inhibition of HMGI-C protein synthesis suppresses retrovirally induced neoplastic transformation of rat thyroid cells. Mol Cell Biol. 1995; 15(3):1545-53. PMC: 230378. DOI: 10.1128/MCB.15.3.1545. View

11.

Chiappetta G, Bandiera A, Berlingieri M, Visconti R, Manfioletti G, Battista S . The expression of the high mobility group HMGI (Y) proteins correlates with the malignant phenotype of human thyroid neoplasias. Oncogene. 1995; 10(7):1307-14. View

12.

Thompson M, Jensen R, Obermiller P, Page D, Holt J . Decreased expression of BRCA1 accelerates growth and is often present during sporadic breast cancer progression. Nat Genet. 1995; 9(4):444-50. DOI: 10.1038/ng0495-444. View

13.

Zhou X, Benson K, Ashar H, Chada K . Mutation responsible for the mouse pygmy phenotype in the developmentally regulated factor HMGI-C. Nature. 1995; 376(6543):771-4. DOI: 10.1038/376771a0. View

14.

Jarvis E, Kirk J, Clarke C . Loss of nuclear BRCA1 expression in breast cancers is associated with a highly proliferative tumor phenotype. Cancer Genet Cytogenet. 1998; 101(2):109-15. DOI: 10.1016/s0165-4608(97)00267-7. View

15.

Sourvinos G, Spandidos D . Decreased BRCA1 expression levels may arrest the cell cycle through activation of p53 checkpoint in human sporadic breast tumors. Biochem Biophys Res Commun. 1998; 245(1):75-80. DOI: 10.1006/bbrc.1998.8379. View

16.

Romagnolo D, Annab L, Thompson T, Risinger J, Terry L, Barrett J . Estrogen upregulation of BRCA1 expression with no effect on localization. Mol Carcinog. 1998; 22(2):102-9. DOI: 10.1002/(sici)1098-2744(199806)22:2<102::aid-mc5>3.0.co;2-o. View

17.

Chiappetta G, Tallini G, De Biasio M, Manfioletti G, Martinez-Tello F, Pentimalli F . Detection of high mobility group I HMGI(Y) protein in the diagnosis of thyroid tumors: HMGI(Y) expression represents a potential diagnostic indicator of carcinoma. Cancer Res. 1998; 58(18):4193-8. View

18.

Magdinier F, Ribieras S, Lenoir G, Frappart L, Dante R . Down-regulation of BRCA1 in human sporadic breast cancer; analysis of DNA methylation patterns of the putative promoter region. Oncogene. 1999; 17(24):3169-76. DOI: 10.1038/sj.onc.1202248. View

19.

Bennett L, Brownlee H, Hagavik S, Wiseman R . Sequence analysis of the rat Brca1 homolog and its promoter region. Mamm Genome. 1999; 10(1):19-25. DOI: 10.1007/s003359900935. View

20.

Wilson C, Ramos L, Villasenor M, Anders K, Press M, Clarke K . Localization of human BRCA1 and its loss in high-grade, non-inherited breast carcinomas. Nat Genet. 1999; 21(2):236-40. DOI: 10.1038/6029. View