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.
Breast cancer gene 1 (BRCA1) on chromosome 17 is responsible for majority of hereditary breast and ovarian cancers (Miki et al., 1994). Among sporadic cases of breast cancer, expression of BRCA1 is reduced or undetectable in high-grade ductal carcinomas, suggesting the involvement of this gene in the etiology of breast cancer. Multiple BRCA1 splice variants are present in different tissues with different expression profiles (Orban and Olah, 2003), but their regulation and functions are not understood at the moment. The presence of these splice variants can create confusion during genetic counseling, because no advice can be given to patients regarding whether variation in their levels can cause breast cancer. Therefore, elucidating the functions of the BRCA1 splice variant would help in understanding the role of this tumor suppressor in breast and ovarian cancers. We have previously isolated and characterized two naturally occurring splice variants of BRCA1, namely BRCA1a/p110 and BRCA1b/p100 (Wang et al., 1997), which form two of the four predominant splice variants present in normal and tumor-derived breast and ovarian cancer cells (Lu et al., 1996; Wilson et al., 1997; Orban and Olah, 2001). Other groups have designated BRCA1a as BRCA1-Δ11b (Wilson et al., 1997), BRCA1s (Lu and Arrick, 2000), BRCA1Δ11q (Orban and Olah, 2001) and BRCA1b as BRCA1s-9,10 (Lu and Arrick, 2000), BRCA1 11qΔ9,10 (Orban and Olah, 2001). BRCA1a differs from BRCA1 in having a deletion of the majority of exon 11 sequences (amino acids 263–1365) and codes for a smaller 110 kDa protein (Figure 1a). Even though the nuclear localization signal sequences are missing from BRCA1a, it still is localized in the nucleus (Wang et al., 1997). Similarly, BRCA1 isoform lacking the exon 11 also enters the nucleus suggesting the presence of a cryptic NLS (Huber et al., 2001). Wild-type BRCA1 and splice variants BRCA1a/1b are multifunctional proteins that interact with several proteins, suggesting that these functions are manifested through association with multiple proteins involved in transcriptional activation/repression, cell-cycle regulation, growth/tumor suppression, apoptosis, DNA repair, genomic stability, steroid hormone receptor signaling and ubiquitination (Welcsh and King, 2001; Rosen et al., 2003). Women carrying BRCA1 mutations typically develop breast tumors that grow rapidly, are grade 3, ductal, ER-negative, progesterone receptor-negative and Her-2 negative (triple-negative (TN) tumors), suggesting that hormonal factors may play a critical role in the development of these cancers (Welcsh and King, 2001; Rosen et al., 2003). Given the role of BRCA1 in tissue-specific tumor suppression (Holt et al., 1996; Aprelikova et al., 1999; Tait et al., 2000; Randrianarison et al., 2001; Marot et al., 2006), we tested the potential for BRCA1a/p110 to function as a tumor inhibitor in estrogen receptor (ER)-positive, TN breast, hormone-independent ovarian and prostate cancer cells. We introduced BRCA1a into these cancer cells and found that stable expression of BRCA1a/p110 resulted in inhibition of cell proliferation and anchorage-independent growth of human breast, ovarian and prostate cancer cells. Furthermore, TN CAL-51, MCF-7 breast cancer cells, ES-2 ovarian carcinoma cells and PC-3 prostate cancer cells transfected with BRCA1a were inhibited in their capacity to form tumors in nude mice. As the majority of exon 11 sequences (residues 263–1365) are deleted in BRCA1a, which includes one of the Rb, p53, c-myc, Rad50, γ-tubulin and angiopoietin-1-binding domains and nuclear localization signal sequences (NLS1 and NLS2). These sequences are not essential for the growth/tumor suppressor function of BRCA1 proteins. Our results demonstrate for the first time that BRCA1 splice variant BRCA1a functions as a growth/tumor suppressor of steroid hormone-independent human breast, ovarian and prostate cancer cells and the Rb pathway but not the p53 status affects the ability of BRCA1a to inhibit tumor growth of cancer cells.
Results and discussion
BRCA1a functions as a growth suppressor in Rb-positive breast, ovarian, prostate, colon, fibroblasts and osteosarcoma cells
BRCA1 has been shown to inhibit the growth of breast, ovarian, lung and colon cancer cells (Holt et al., 1996; Aprelikova et al., 1999; Tait et al., 2000; Randrianarison et al., 2001; Marot et al., 2006). Others have found BRCA1 to inhibit the growth of a number of cell lines with an Rb-positive and p53-negative background (Aprelikova et al., 1999; Randrianarison et al., 2001). Our earlier results demonstrate that inhibition of expression of endogenous BRCA1 in mouse fibroblast results in transformation (Rao et al., 1996) and high-level expression of BRCA1a in breast cancer cells decreases proliferation (Chai et al., 2001) and induces apoptosis (Shao et al., 1996). In an attempt to understand whether BRCA1a can function as a growth suppressor similar to BRCA1, we have transfected BRCA1a (pcDNA3-BRCA1a) into a number of cell lines with known status of tumor suppressor genes, such as p53 and pRb. Cells were transfected with either a BRCA1a expression vector or empty vector and selected with G-418 and the colonies were scored after 18–21 days following staining with crystal violet. Overexpression of BRCA1a in cells with wild-type pRb resulted in a 38–44% reduction in the number of G418-resistant colonies compared with vector alone (Figure 1b). Three cells lines with either deletion in the Rb gene (Saos2 and DU145) or inactivation of the Rb, because of the presence of SV40 (HBL100), showed insignificant difference in the number of colonies formed after transfection with BRCA1a compared with the control emphasizing the role of Rb in BRCA1a-mediated growth inhibition. Similar results were obtained previously by Aprelikova et al. (1999) using the BRCA1 expression vector. These investigators observed that deletion of amino acids 303–394 from BRCA1 resulted in loss of growth suppression in U2OS cells, but we have found BRCA1a to inhibit growth of breast, ovarian, prostate, colon and other cells. These results suggest that the majority of exon 11 sequences that are deleted in BRCA1a may not be required for growth inhibition, but the second Rb-binding domain present in the carboxyl terminus of BRCA1a may be important for the growth suppressor function of this protein.
The growth suppression of BRCA1a is p53 independent
BRCA1 protein has been shown to associate both in vitro and in vivo with p53 and coactivates transcription from the p53-responsive promoters (Somasundaram et al., 1997; Ouichi et al., 1998; Zhang et al., 1998). Several groups have shown that BRCA1 regulates p21 WAFI/CIPI through both p53-dependent and p53-independent mechanisms. Harkin et al. (1999) have observed neither activation nor repression of p53 and p21 following inducible expression of BRCA1. As BRCA1a contains one of the p53-interaction domains and activates p21 WAF1/CIP1 transcription in a p53-dependent manner, we speculated that it can regulate cell proliferation through a p53-dependent mechanism. However, several cell lines in our panel (Figure 1b) had a normal Rb and a mutated p53 gene (ES-2, PC-3, CAMA-1, ZR75-1 and COLO-320), and all these cells showed growth suppression in the presence of BRCA1a. These results suggest that the antiproliferative activity observed with BRCA1a is independent of the p53–p21 pathway. Randrianarison et al. (2001) reached a similar conclusion with BRCA1.
Development of stable BRCA1a-expressing human ER-positive, TN breast, hormone-independent ovarian and prostate cancer cell lines
Holt et al. (1996) used a retroviral vector to deliver BRCA1 into ER-positive human breast and ovarian cancer cells to show that it functions as a tumor suppressor. CAL51 is an ideal breast cancer cell line derived from the pleural effusion of a 45-year-old patient with invasive adenocarcinoma with extensive intraductal involvement. It is epithelial, with a normal diploid karyotype, luminal phenotype negative for both ER and PR (Table 1A). Our results using semiquantitative immunocytochemistry show CAL51 to be negative for HER2 based on (0) staining intensity (Table 1A). TN breast cancers are a group of cancers with poor prognosis, prevention and treatments compared to ER-positive tumors and occur very often in women carrying BRCA1 mutation (Tischkowitz and Foulkes, 2006). In an attempt to understand the role of BRCA1a in tumor suppression, we have transfected breast cancer cell lines MCF-7 (ER-positive) and CAL51 (TN), and hormone-independent ovarian cancer cell line ES-2 and hormone-independent prostate cancer cell line PC-3 with pcDNA expression vector or pCDNA expression vector containing human BRCA1a cDNA, and obtained stable G418-resistant cell lines expressing BRCA1a. The morphology of the BRCA1a transfectants was different from that of the parental CAL-51, MCF-7, and ES-2 and PC-3 cells. The BRCA1a transfectants were slow-growing and appeared to be shorter and flatter compared to the parental CAL-51, MCF-7, ES-2 and PC-3 cells (date not given). These MCF-7/CAL-51/ES-2/PC-3-BRCA1a cell lines were analysed for BRCA1a protein expression by immunoperoxidase staining and Western blot analysis using BRCA1 polyclonal antibody as described previously (Wang et al., 1997). The nuclear and cytoplasmic staining was brighter and stronger in CAL51-BRCA1a transfectants compared to CAL-51-pcDNA cells (Figure 2) suggesting higher levels of expression of BRCA1a protein in the transfected cells. Western blot analysis revealed a significant increase in the levels of expression of BRCA1a proteins when compared to vector-transfected MCF-7 (Figure 2a), ES-2 (Figure 2c) and PC-3 cells (Figure 2c).
Overexpression of BRCA1a inhibits proliferation and transformation in vitro of MCF-7, CAL-51 breast cancer cells, ES-2 ovarian cancer cell and PC-3 prostate cancer cells
Upon establishment of the BRCA1a expressing cells, we studied the growth properties of these transfectants. Transfected MCF-7 cells and CAL-51 breast cancer cells were found to grow more slowly in higher (10%) serum compared to vector-transfected controls (Figure 3a and b). Similar growth inhibition was observed in the ES-2 ovarian cancer clones and PC-3 prostate cancer clones compared to the respective vector-transfected clones (Figure 3c and d). These results suggest that overexpression of BRCA1a decreases proliferation in vitro of breast, ovarian and prostate cancer cells. These results are consistent with previous reports on the negative cell growth regulatory properties of BRCA1 (Holt et al., 1996; Aprelikova et al., 1999; Tait et al., 2000; Randrianarison et al., 2001; Marot et al., 2006). We next tested their ability to grow in soft agar. All BRCA1a transfectants (MCF-7, CAL-51, ES-2 and PC-3) were inhibited in their capacity to form colonies in soft agar (Figure 4a–d). These results demonstrate that BRCA1a functions as a tumor suppressor in vitro on human breast, ovarian and prostate cancer cells, and the majority of exon 11 sequences that are deleted in BRCA1a (Figure 1a) are not required for the tumor suppressor function of this protein.
BRCA1a inhibits tumor development in vivo in nude mice
We analysed the tumorigenicity in vivo of CAL-51, ES-2 and PC-3 cells transfected with either pCDNA or BRCA1a in immunodeficient nude mice. As shown in Table 1B, subcutaneous injection of pCDNA-transfected CAL-51, ES-2 and PC-3 cells into nude mice resulted in the development of tumors within 2 weeks (four out of four animals). None of the mice injected with the BRCA1a transfectants induced tumors at least up to 6 weeks (four out of four animals). These results suggest that BRCA1a functions as a tumor suppressor in vivo in nude mice.
In this paper, we have demonstrated for the first time that BRCA1 splice variant BRCA1a can significantly inhibit the growth of ER-positive MCF-7, TN CAL51 breast cancer cells, hormone-independent ES-2 ovarian and PC-3 prostate cancer cells. As BRCA1a lacks majority of exon 11 sequences (263–1365), which include one of the Rb-binding domains (amino acids 304–394) and p53 interaction domains (amino acids 224–500), c-myc (amino acids 433–511), γ tubulin (amino acids 504–803), STAT1 (amino acids 502–802), RAD 51 (amino acids 758–1064), RAD50 (amino acid 341–748)-binding domains and nuclear localization signal sequences (Welcsh and King, 2001; Rosen et al., 2003) suggest that this region of exon 11 is dispensable for the tumor suppressor function of BRCA1 protein. We can speculate that mutations that are present in the patient within the exon 11 region (residues 263–1365) may not be functionally significant for the tumor suppressor activity of this gene. Recently, expression of an N-terminal BRCA1 deletion mutant in adenoviral vector resulted in a powerful growth inhibition in MCF10A cells (You et al., 2004). On the basis of these findings, it was suggested that the N-terminal domain may regulate the growth inhibitory activity of the internal domain. This internal domain (residues 303–1292) is lost in BRCA1a as a result of alternative splicing and it still functions as a growth suppressor. Our results also demonstrated that the growth suppressor function of BRCA1a is dependent on the presence of Rb similar to BRCA1 (Aprelikova et al., 1999). It could be possible that the second Rb-binding domain (residues 1636–1863) found in the Cl terminus of BRCA1, which associates with the histone deacetylases repressing transcription of growth promoting genes (Yarden and Brody, 1998), may be critical for the antitumor activity of BRCA1 proteins. Majority of BRCA1-related breast cancers have a typical basal epithelial phenotype, TN, grade 3 and are more prevalent in younger African-American women (Tischkowitz and Foulkes, 2006). There are currently no treatments that are effective against TN breast cancers. One of the challenges in breast cancer research is to discover new drugs or treatment strategies that will be effective against TN breast and hormone-independent ovarian and prostate tumors. Results from these studies will provide new avenues in the future for molecular diagnosis and treatment of these cancers. Finally, as BRCA1a was found to be greatly reduced or absent in several breast and ovarian tumors relative to BRCA1, we can speculate that variation in the levels of expression of these isoforms can result in cancer. Such a finding would expedite the development of diagnostic tests, which will aid counseling of families with family history of breast cancer.
Materials and methods
Human breast carcinoma cell lines (MCF-7, CAMA-1, ZR75-1 and HCC-1937), HBL100 (normal breast epithelial cells immortalized with SV40), NIH3T3 fibroblasts, COLO320 (colon cancer), ES-2 (ovarian cancer), PC-3 and DU145 (prostate cancer) and Saos2 (osteosarcoma) cells were obtained from American Type Culture Collection (Rockville, MD, USA). Mouse embryo fibroblasts were obtained from Tyler Jacks (MIT, Boston, MA, USA).
Purified DNA (10–20 μg) of pCDNA3 expression vector or vector containing the full-length BRCA1a CDNA were transfected into MCF7, CAL51, ES-2 and PC-3 cells using calcium phosphate according to the manufacturer's instructions (Promega Corporation, Madison, WI, USA). Selection with 800 μg/ml G418 was started 48 h after transfection. After 3–4 weeks, G418-resistant colonies were picked and further propagated in selective medium as described previously (Rao et al., 1996).
MTT growth assay
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) metabolic assay was performed as described (Chai et al., 2001). In brief, pcDNA or BRCA1a-transfected MCF-7, CAL51, ES-2 and PC3 cells were split at a density of 1 × 104 cells into microtiter plates and incubated in media containing 10% fetal bovine serum (FBS) at 37°C with 5% Co2. At five 24 h intervals, viable cells were stained for 4 hours with MTT dye and absorbance was read at 570 nm. The experiments were performed in triplicates and repeated at least three times.
Soft agar assay
Soft agar assay was carried out using 0.3% agar/Dulbecco's modified Eagle's medium (DMEM)/10% FBS and plated on a base of 0.5% agar/DMEM or McCoy's 5a or Ham's F12K/10% FBS as described previously (Rao et al., 1996). Cells were plated at a concentration of 1 × 104 per 35 mm plate in soft agar containing complete media and kept at 37°C in CO2 incubator adding a few drops of media every week. Colonies greater than 80 μm in diameter were scored after 3 weeks. Each soft agar assay was performed in triplicate.
Colony suppression assay
MCF-7, CAL-51, ES-2, PC-3, NIH3T3, COLO320, CAMA-1, ZR75-1, Mouse embryo fibroblasts p53−/−, DU145, Saos2 and HBL100 cells were plated at a concentration of 1.5 × 105 cells per 100 mm plate, 10 ml of complete media and transfected with either pcDNA3 or pcDNA BRCA1a by using the calcium phosphate kit from Promega. Thirty-six to forty-eight hours later cells were trypsinized and plated directly into complex medium containing 50–800 μg/ml G418. Cells were fed fresh medium containing G418 every 3–4 days. Cells were stained for colonies approximately 21 days after transfections using crystal violet blue as described previously (Chai et al., 2001).
Nude mice assay
CAL-51, ES-2 and PC-3 stable cells transfected with empty DNA vector or with BRCA1a were typsinized, washed and suspended in sterile phosphate-buffered saline solution. To determine their tumorigenicity, suspension of 1 × 107 cells in a volume of 0.2 ml of phosphate-buffered saline was injected subcutaneously above the hindleg of 4–5-week-old female immunodeficient nude mice (Ncr-mu). The mice were examined for tumor development every week for up to 6 weeks. The tumors were allowed to grow to at least 1.5–2.0 cm in diameter before killing.
Preparation of cell lysates and western blot analysis
To the cell pellets, cold radioimmuno precipitation assay buffer containing protease inhibitors was added. This was mixed gently, incubated on ice for 30 min and passed through a 21-gauge needle to shear the DNA. A total of 10 μl of 10 mg/ml phenylmethylsulphonyl fluoride stock was added and incubated on ice for a further 30 min. Cell lysates were centrifuged at 15 000 g for 20 min at 4°C. The supernatant was the cell lysate that was used for Western blotting. Western blot analysis was carried out essentially as described (Wang et al., 1997). In brief, ∼90 μg of protein from each of the extracts was loaded on a 10% sodium dodecyl sulfate-polyacrylamide gel electrophoresis as described previously (Wang et al., 1997). After electro transfer onto nitrocellulose membrane, the filter was probed with a polyclonal BRCA1 peptide antibody D-20 or actin antibody (Santa Cruz Biotechnology, inc., Santa Cruz, CA, USA) as described by the manufacturer (ECL Kit, Amersham Biosciences, Pitscataway, NJ, USA) and exposed to Kodak X-AR film.
Cal51 cells stably overexpressing the BRCA1a protein were grown at 37°C in DMEM medium containing 10% FBS, 0.6 μg/ml bovine insulin, 5 × 10−3 μg/ml transferring, 1% penicillin–streptomycin and 200 μg/ml of G418. Cells were cultured in chamber slides and processed for immunohistochemistry using BRCA1 peptide antibody D-20 as described previously (Wang et al., 1997). For Her-2 expression Cal51 cells were pelleted, fixed in 10% neutral buffered formalin, embedded in paraffin and the slides were analysed by immunohistochemistry using the Hercept test kit supplied by DAKO Corporation (Carpinteria, CA, USA). The Her-2 protein overexpression was interpreted as negative based on (0) staining intensity.
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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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Cite this article
Yuli, C., Shao, N., Rao, R. et al. BRCA1a has antitumor activity in TN breast, ovarian and prostate cancers. Oncogene 26, 6031–6037 (2007) doi:10.1038/sj.onc.1210420
- ovarian cancers
- prostate cancer
- tumor suppressor
- estrogen receptor
- triple-negative breast cancers
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