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Molecular and Cellular Biology, April 2003, p. 2225-2238, Vol. 23, No. 7
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.7.2225-2238.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

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

Gustavo Baldassarre,1,{dagger} Sabrina Battista,1,2 Barbara Belletti,1,{dagger} Sanjay Thakur,1 Francesca Pentimalli,1,2 Francesco Trapasso,1 Monica Fedele,2 Giovanna Pierantoni,2 Carlo M. Croce,1 and Alfredo Fusco2*

Kimmel Cancer Center, Jefferson Medical College, Philadelphia, Pennsylvania 19107,1 Dipartimento di Biologia e Patologia Cellulare e Molecolare c/o Centro di Endocrinologia ed Oncologia Sperimentale del CNR, Facoltà di Medicina e Chirurgia, Università degli Studi di Napoli "Federico II," 80131 Naples, Italy2

Received 16 September 2002/ Returned for modification 29 October 2002/ Accepted 26 December 2002

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.

* Corresponding author. Mailing address: Dipartimento di Biologia e Patologia Cellulare e Molecolare, Facoltà di Medicina e Chirurgia di Napoli, via Pansini 5, 80131 Naples, Italy. Phone: 39-081-7463749. Fax: 39-081-7463037. E-mail: afusco{at}napoli.com.

{dagger} Present address: Divisione di Oncologia Sperimentale 2, Centro di Riferimento Oncologico, Aviano 33081, Italy.

Molecular and Cellular Biology, April 2003, p. 2225-2238, Vol. 23, No. 7
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.7.2225-2238.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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