Abstract
Breast cancer gene 1 (BRCA1) mutations predispose women to breast and ovarian cancers and men to increased risks for prostate cancer. We have previously showed BRCA1 splice variant BRCA1a/p110 to induce apoptosis of human breast cancer cells. In the current study, stable expression of BRCA1a/p110 resulted in inhibition of growth of estrogen receptor (ER)-positive and triple-negative (TN) human breast, ovarian, prostate and colon cancer cells and mouse fibroblast cells. Similar to wild-type BRCA1, only those cells with wild-type Rb were sensitive to BRCA1a-induced growth suppression and the status of p53 did not affect the ability of BRCA1a to suppress growth of tumor cells. BRCA1a also significantly inhibited tumor mass in nude mice bearing human CAL-51 TN breast cancer, ES-2 ovarian cancer and PC-3 prostate cancer xenografts. These results suggest that the majority of exon 11 sequences (residues 263–1365) are not required for the tumor suppressor function of BRCA1 proteins. This is the first report demonstrating antitumor activity of BRCA1a in human ER-positive and TN breast, hormone-independent ovarian and prostate cancer cells. Currently, there are no effective treatments against TN breast cancers and results from these studies will provide new treatments for one of the biggest needs in breast cancer research.
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References
Aprelikova ON, Fan BS, Meissner EG, Cotter S, Campbell M, Kuthiala A et al. (1999). BRCA1 associated growth arrest is RB-dependent. PNAS 96: 11867–11871.
Chai YL, Cui J, Chipitsyna G, Liao B, Lui S, Aysola K et al. (2001). C-Fos oncogene regulator Elk-1 interacts with BRCA1 splice variants BRCA1a/1b and enhances BRCA1a/1b mediated growth suppression in breast cancer cells. Oncogene 20: 1357–1367.
Gioanni J, le Francois D, Zanghellini E, Mazeau C, Ettore F, Lambert JC et al. (1990). Establishment and characterization of a new tumorigenic cell line with normal karyotype derived from a human breast adenocarcinoma. Br J Cancer 62: 8–13.
Grunberg E, Eckert K, Karsten U, Maurer HR . (2000). Effects of differentiated inducers on cell phenotypes of cultured non transformed and immortalized memory epithelial cells: a comparative immunocytochemical analysis. Tumor Biology 4: 211–223.
Harkin DP, Bean JM, Miklos D, Song YH, Truong VB, Englert C et al. (1999). Induction of GADD45 and JNK/SAPK-dependent apoptosis following inducible expression of BRCA1. Cell 5: 575–586.
Holt JT, Thompson ME, Szabo C, Robinson-Benion C, Arteaga CL, King MC et al. (1996). Growth retardation and tumor inhibition by BRCA1 Nat. Genetics 12: 298–302.
Huber LJ, Yang TW, Sarkisian CJ, Master SR, Deng CX, Chodosh LA . (2001). Impaired DNA damage response in cells expressing an exon 11-deleted murine BRCA1 variant that localizes to nuclear foci. Mol Cell Biol 21: 4005–4015.
Lu M, Arrick BA . (2000). Transactivation of the p21 promoter by BRCA1 splice variants in mammary epithelial cells: evidence for both common and distinct activities of wildtype and mutant forms. Oncogene 19: 6351–6360.
Lu M, Conzen SD, Cole CN, Arrick B . (1996). Characterization of functional messenger RNA splice variants of BRCA1 expressed in non malignant and tumor-derived breast alls. Cancer Res 56: 4578–4581.
Marot D, Opolon P, Brailly Tabard S, Elie N, Randrianarison V, Connault E et al. (2006). The tumor suppressor activity induced by adenovirus mediated BRCA1 over expression is not restricted to breast cancers. Gene Ther 13: 235–244.
Miki Y, Swensen J, Shattuck-Eidens D, Futreal PA, Harshman K, Tavitigan S et al. (1994). A strong candidate for the breast and ovarian cancer susceptibility gene BRCA1. Science 266: 66–71.
Orban TI, Olah E . (2001). Expression profiles of BRCA1 splice variants in a synchronous and in G1/S synchronized tumor cell lines. BBRC 280: 32–38.
Orban TI, Olah E . (2003). Emerging roles of BRCA1 alternative splicing. Mol Path 56: 191–197.
Ouichi T, Monteiro AN, August A, Aaronson SA, Hanafusa H . (1998). BRCA1 regulates p53-dependent gene expression. PNAS USA 95: 2302–2306.
Randrianarison V, Marot D, Foray N, Cabannes J, Meret V, Connault E et al. (2001). BRCA1 carries tumor suppressor activity distinct from that of p53 and p21. Cancer Gene Ther 8: 759–770.
Rao VN, Shao N, Ahmed M, Reddy ESP . (1996). Antisense RNA to putative tumor suppressor gene BRCA1 transforms mouse fibroblast. Oncogene 12: 523–528.
Rosen EM, Fan S, Pestell RG, Goldberg ID . (2003). BRCA1 gene in breast cancer. J Cell Physiol 196: 19–41.
Shao N, Chai YL, Reddy ESP, Rao VN . (1996). Induction of apoptosis by the tumor suppressor protein BRCA1. Oncogene 13: 1–7.
Somasundaram K, Zhang H, Zeng YX, Houvras Y, Peng Y, Zhang H et al. (1997). Arrest of the cell cycle by the tumor-suppressor BRCA1 requires the CDK-inhibitor p21WAF1/CiP1. Nature 389: 187–190.
Tait DL, Obermiller PS, Holt JT . (2000). Preclinical studies of a new generation retroviral vector for ovarian cancer BRCA1 gene therapy. Gynecol Oncol 79: 471–476.
Theile M, Hartmann S, Scherthan H, Arnold W, Deppert W, Frege R et al. (1995). Suppression of tumorigenicity of breast cancer cells by transfer of human chromosome 17 does not require transferred BRCA1 and p53 genes. Oncogene 10: 439–447.
Tischkowitz MD, Foulkes WD . (2006). The basal phenotype of BRCA1-related breast cancer: past, present and future. Cell Cycle 5: 963–967.
Wang H, Shao N, Ding OM, Cui J, Reddy ESP, Rao VN . (1997). BRCA1 proteins are transported to the nucleus in the absence of serum and splice variants BRCA1a, BRCA1b are tyrosine phosphoprotein that associate with E2F, cyclins and cyclin dependent Kinases. Oncogene 15: 143–157.
Welcsh PL, King MC . (2001). BRCA1 and BRCA2 and the genetics of breast and ovarian cancer. Hum Mol Gen 10: 705–713.
Wilson CA, Payton MN, Elliott ES, Buaas FW, Cajulis EE, Grosshans D et al. (1997). Differential sub cellular, localization, expression and biological toxicity of BRCA1 and the splice variant BRCA1-delta 11b. Oncogene 14: 1–16.
Yarden RI, Brody LC . (1998). BRCA1 interacts with components of the histone deacetylase complex. PNAS 96: 4983–4988.
You F, Chiba N, Ishioka C, Parvin JD . (2004). Expression of an amino-terminal BRCA1 deletion mutant causes a dominant growth inhibition in MCF10A cells. Oncogene 23: 5792–5798.
Zhang H, Somasundaram K, Peng Y, Tian H, Zhang H, Bi D et al. (1998). BRCA1 physically associates with p53 and stimulates its transcriptional activity. Oncogene 16: 1713–1721.
Acknowledgements
We thank J Gioanne and Jean Louis Fischel of Oncopharmacologic laboratories for the CAL-51 cell line and Tyler Jacks for the p53−/− mouse embryo fibroblasts. We thank Kashwayne Williams for secretarial assistance. We also thank all the other members of Rao and Reddy labs for their help. VNR dedicates this paper to her mother Rohini N Rao. This work was funded in part by Georgia Cancer Coalition Distinguished Cancer Scholar Award, NIH Ovarian Cancer Spore grant to VN Rao and Georgia Cancer Coalition Distinguished Cancer Scholar Award to ESP Reddy. This work was supported in part by NIH-NCRR-RCMI grants G-12-RR03034 and SP20RR11104.
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Yuli, C., Shao, N., Rao, R. et al. BRCA1a has antitumor activity in TN breast, ovarian and prostate cancers. Oncogene 26, 6031–6037 (2007). https://doi.org/10.1038/sj.onc.1210420
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DOI: https://doi.org/10.1038/sj.onc.1210420
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