BRCA1 and BRCA2 as molecular targets for phytochemicals indole-3-carbinol and genistein in breast and prostate cancer cells

S Fan, Q Meng, K Auborn, T Carter, E M Rosen, S Fan, Q Meng, K Auborn, T Carter, E M Rosen

Abstract

Indole-3-carbinol (I3C) and genistein are naturally occurring chemicals derived from cruciferous vegetables and soy, respectively, with potential cancer prevention activity for hormone-responsive tumours (e.g., breast and prostate cancers). Previously, we showed that I3C induces BRCA1 expression and that both I3C and BRCA1 inhibit oestrogen (E2)-stimulated oestrogen receptor (ER-alpha) activity in human breast cancer cells. We now report that both I3C and genistein induce the expression of both breast cancer susceptibility genes (BRCA1 and BRCA2) in breast (MCF-7 and T47D) and prostate (DU-145 and LNCaP) cancer cell types, in a time- and dose-dependent fashion. Induction of the BRCA genes occurred at low doses of I3C (20 microM) and genistein (0.5-1.0 microM), suggesting potential relevance to cancer prevention. A combination of I3C and genistein gave greater than expected induction of BRCA expression. Studies using small interfering RNAs (siRNAs) and BRCA expression vectors suggest that the phytochemical induction of BRCA2 is due, in part, to BRCA1. Functional studies suggest that I3C-mediated cytoxicity is, in part, dependent upon BRCA1 and BRCA2. Inhibition of E2-stimulated ER-alpha activity by I3C and genistein was dependent upon BRCA1; and inhibition of ligand-inducible androgen receptor (AR) activity by I3C and genistein was partially reversed by BRCA1-siRNA. Finally, we provide evidence suggesting that the phytochemical induction of BRCA1 expression is due, in part, to endoplasmic reticulum stress response signalling. These findings suggest that the BRCA genes are molecular targets for some of the activities of I3C and genistein.

Figures

Figure 1
Figure 1
Indole-3-carbinol (I3C) upregulates BRCA1 and BRCA2 mRNA expression in human breast cancer cells in a time- and dose-dependent manner. For time course studies, subconfluent proliferating MCF-7 (A) or T47D (B) cells were treated with I3C (60 μM) for different times and harvested for mRNA analysis by semiquantitative RT–PCR. For dose–response studies, MCF-7 (C) or T47D (D) cells were treated with different doses of I3C for 24 h and harvested for mRNA analysis. The PCR bands were quantified by densitometry and expressed relative to the control gene, β-actin. The densitometry values are means±s.e.m.'s of at least two independent experiments.
Figure 2
Figure 2
Indole-3-carbinol upregulates BRCA1 and BRCA2 protein levels in human breast and prostate cancer cells in a time- and dose-dependent manner. For time course studies, subconfluent proliferating MCF-7 (A), T47D (B), DU-145 (E), and LNCaP (F) cells were treated with I3C (60 μM) for various times and harvested for Western blot analysis to detect the BRCA1, BRCA2, or actin (control for loading and transfer) proteins. For dose–response studies, MCF-7 (C), T47D (D), DU-145 (G), or LNCaP (H) cells were treated with the indicated dose of I3C for 24 h and then assayed for BRCA1 and BRCA2 protein expression. The protein bands were quantitated by densitometry and expressed relative to actin. The densitometry values are means±s.e.m.'s of at least two independent experiments.
Figure 2
Figure 2
Indole-3-carbinol upregulates BRCA1 and BRCA2 protein levels in human breast and prostate cancer cells in a time- and dose-dependent manner. For time course studies, subconfluent proliferating MCF-7 (A), T47D (B), DU-145 (E), and LNCaP (F) cells were treated with I3C (60 μM) for various times and harvested for Western blot analysis to detect the BRCA1, BRCA2, or actin (control for loading and transfer) proteins. For dose–response studies, MCF-7 (C), T47D (D), DU-145 (G), or LNCaP (H) cells were treated with the indicated dose of I3C for 24 h and then assayed for BRCA1 and BRCA2 protein expression. The protein bands were quantitated by densitometry and expressed relative to actin. The densitometry values are means±s.e.m.'s of at least two independent experiments.
Figure 3
Figure 3
Genistein upregulates BRCA1 and BRCA2 protein levels in breast cancer cells. For time course studies, subconfluent proliferating MCF-7 (A), T47D (B), DU-145 (E), and LNCaP (F) cells were treated with genistein (5 μM) for the indicated times and harvested for Western blotting to detect the BRCA1, BRCA2, or actin proteins. For dose–response studies, MCF-7 (C), T47D (D), DU-145 (G), or LNCaP (H) cells were treated with the indicated dose of genistein for 24 h and assayed for BRCA1 and BRCA2 protein expression, as described above. The densitometry values represent means±s.e.m.'s of at least two independent experiments.
Figure 3
Figure 3
Genistein upregulates BRCA1 and BRCA2 protein levels in breast cancer cells. For time course studies, subconfluent proliferating MCF-7 (A), T47D (B), DU-145 (E), and LNCaP (F) cells were treated with genistein (5 μM) for the indicated times and harvested for Western blotting to detect the BRCA1, BRCA2, or actin proteins. For dose–response studies, MCF-7 (C), T47D (D), DU-145 (G), or LNCaP (H) cells were treated with the indicated dose of genistein for 24 h and assayed for BRCA1 and BRCA2 protein expression, as described above. The densitometry values represent means±s.e.m.'s of at least two independent experiments.
Figure 4
Figure 4
Dependence of phytochemical-induced expression of BRCA2 on BRCA1. (A) BRCA1-siRNA causes time-dependent loss of BRCA1 and BRCA2 in MCF-7 cells. Subconfluent proliferating cells were treated with BRCA1-siRNA (left) or control-siRNA (right) (50 nM) for different times, harvested, and Western blotted for BRCA1, BRCA2, and actin. (B) Effect of BRCA1-siRNA on BRCA2 protein levels and vice versa in DU-145 cells. Cells were treated with BRCA1, BRCA2, or control-siRNA (50 nM) for 72 h and Western blotted for BRCA1, BRCA2, and actin. Results are shown for two separate cell treatments and protein isolations on the same blot. (C) Effect of wtBRCA1 on BRCA2 protein levels and vice versa in DU-145 cells. Cells were transfected overnight with wtBRCA1, wtBRCA2, or empty pcDNA3 vector, washed, postincubated for 24 h to allow gene expression, harvested, and Western blotted for BRCA1, BRCA2, and actin. Results are shown for two separate cell treatments and protein isolations on the same blot. The densitometry values are means±ranges of two experiments. (D) Effect of BRCA1 and BRCA2 siRNAs on BRCA induction by I3C. DU-145 cells were preincubated with the indicated siRNA (50 nM × 72 h) or no siRNA (transfection reagent only), then treated with I3C (40 μM) for 24 h, and then harvested for Western blotting. (E) Effect of BRCA1 and BRCA2 siRNA on induction of BRCA1 and BRCA2 by genistein. DU-145 cells were preincubated with the indicated siRNA (50 nM × 72 h), treated with genistein (5 μM) for 24 h, and harvested for Western blotting as above. (F) Induction of BRCA1 and BRCA2 by a combination of I3C plus genistein. MCF-7 or DU-145 cells were treated with low doses of I3C (25 μM) and/or genistein (1 μM) for 24 h and harvested for Western blotting. The densitometry values are means±ranges of two independent experiments. (G) Effect of ICI182,780 on phytochemical induction of BRCA1 in MCF-7 cells. Proliferating cells were incubated with the indicated agents for 24 h and then harvested for Western blotting for BRCA1, ER-α, or actin. (H) Effect of BRCA1 knockdown and phytochemicals on ER-α protein levels. MCF-7 cells were pretreated with BRCA1 or control siRNA as described above, exposed to the indicated doses of I3C or genistein for 24 h, and then Western blotted for ER-α, BRCA1, or actin.
Figure 4
Figure 4
Dependence of phytochemical-induced expression of BRCA2 on BRCA1. (A) BRCA1-siRNA causes time-dependent loss of BRCA1 and BRCA2 in MCF-7 cells. Subconfluent proliferating cells were treated with BRCA1-siRNA (left) or control-siRNA (right) (50 nM) for different times, harvested, and Western blotted for BRCA1, BRCA2, and actin. (B) Effect of BRCA1-siRNA on BRCA2 protein levels and vice versa in DU-145 cells. Cells were treated with BRCA1, BRCA2, or control-siRNA (50 nM) for 72 h and Western blotted for BRCA1, BRCA2, and actin. Results are shown for two separate cell treatments and protein isolations on the same blot. (C) Effect of wtBRCA1 on BRCA2 protein levels and vice versa in DU-145 cells. Cells were transfected overnight with wtBRCA1, wtBRCA2, or empty pcDNA3 vector, washed, postincubated for 24 h to allow gene expression, harvested, and Western blotted for BRCA1, BRCA2, and actin. Results are shown for two separate cell treatments and protein isolations on the same blot. The densitometry values are means±ranges of two experiments. (D) Effect of BRCA1 and BRCA2 siRNAs on BRCA induction by I3C. DU-145 cells were preincubated with the indicated siRNA (50 nM × 72 h) or no siRNA (transfection reagent only), then treated with I3C (40 μM) for 24 h, and then harvested for Western blotting. (E) Effect of BRCA1 and BRCA2 siRNA on induction of BRCA1 and BRCA2 by genistein. DU-145 cells were preincubated with the indicated siRNA (50 nM × 72 h), treated with genistein (5 μM) for 24 h, and harvested for Western blotting as above. (F) Induction of BRCA1 and BRCA2 by a combination of I3C plus genistein. MCF-7 or DU-145 cells were treated with low doses of I3C (25 μM) and/or genistein (1 μM) for 24 h and harvested for Western blotting. The densitometry values are means±ranges of two independent experiments. (G) Effect of ICI182,780 on phytochemical induction of BRCA1 in MCF-7 cells. Proliferating cells were incubated with the indicated agents for 24 h and then harvested for Western blotting for BRCA1, ER-α, or actin. (H) Effect of BRCA1 knockdown and phytochemicals on ER-α protein levels. MCF-7 cells were pretreated with BRCA1 or control siRNA as described above, exposed to the indicated doses of I3C or genistein for 24 h, and then Western blotted for ER-α, BRCA1, or actin.
Figure 5
Figure 5
Contribution of BRCA1 and BRCA2 to I3C-mediated cytotoxicity. (A) The effects of BRCA1-siRNA (48 and 72 h) and BRCA2-siRNA (72 h) (50 nM) on BRCA1 and BRCA2 protein levels, respectively, in MCF-7 cells. MCF-7 (B and C), T47D (D and E), and DU-145 (F and G) cells were experimentally manipulated to increase (wtBRCA1) or decrease (BRCA1-siRNA) BRCA1 levels, treated with different doses of I3C, and tested for cell viability using MTT assays. In (H) and (I), DU-145 cells were manipulated to increase (wtBRCA2) or decrease (BRCA2-siRNA) BRCA2 levels, exposed to different doses of I3C, and tested for cell viability using MTT assays. Methodology (B–I). To increase BRCA1 levels, subconfluent cells in 96-well dishes were transfected with wtBRCA1 overnight (see Materials and Methods), washed, postincubated for 24 h, exposed to different doses of I3C for 24 h, and assayed for MTT dye reduction. To decrease BRCA1 levels, cells were pretreated with BRCA1- or control-siRNA (50 nM × 72 h) or mock-transfected (control) and assayed for sensitivity to I3C as above. For BRCA2 experiments, DU-145 cells were transfected with wtBRCA2 or treated with BRCA2- or control-siRNA (as above) and assayed as described above for sensitivity to I3C. Cell viability values are expressed relative to the 0 I3C control and are means±s.e.m.'s for 10 replicate wells. Statistical comparisons. Cell viability comparisons were made using two-tailed t-tests. Significant differences were as follows: MCF-7 wtBRCA1 vs control, P<0.001 at 100–400 μM I3C; MCF-7 BRCA1-siRNA vs control, P<0.001 at 200–500 μM I3C; T47D wtBRCA1 vs control, P<0.001 at 100–500 μM I3C; T47D BRCA1-siRNA vs control, P<0.001 at 200–500 μM I3C; DU-145 wtBRCA1 vs control, P<0.001 at 100–400 μM I3C; DU-145 BRCA1-siRNA vs control, P<0.001 at 100–500 μM I3C; DU-145 wtBRCA1 vs control, P<0.001, 100–400 μM I3C; and DU-145 BRCA2-siRNA vs control, P<0.001 at 200–500 μM I3C.
Figure 5
Figure 5
Contribution of BRCA1 and BRCA2 to I3C-mediated cytotoxicity. (A) The effects of BRCA1-siRNA (48 and 72 h) and BRCA2-siRNA (72 h) (50 nM) on BRCA1 and BRCA2 protein levels, respectively, in MCF-7 cells. MCF-7 (B and C), T47D (D and E), and DU-145 (F and G) cells were experimentally manipulated to increase (wtBRCA1) or decrease (BRCA1-siRNA) BRCA1 levels, treated with different doses of I3C, and tested for cell viability using MTT assays. In (H) and (I), DU-145 cells were manipulated to increase (wtBRCA2) or decrease (BRCA2-siRNA) BRCA2 levels, exposed to different doses of I3C, and tested for cell viability using MTT assays. Methodology (B–I). To increase BRCA1 levels, subconfluent cells in 96-well dishes were transfected with wtBRCA1 overnight (see Materials and Methods), washed, postincubated for 24 h, exposed to different doses of I3C for 24 h, and assayed for MTT dye reduction. To decrease BRCA1 levels, cells were pretreated with BRCA1- or control-siRNA (50 nM × 72 h) or mock-transfected (control) and assayed for sensitivity to I3C as above. For BRCA2 experiments, DU-145 cells were transfected with wtBRCA2 or treated with BRCA2- or control-siRNA (as above) and assayed as described above for sensitivity to I3C. Cell viability values are expressed relative to the 0 I3C control and are means±s.e.m.'s for 10 replicate wells. Statistical comparisons. Cell viability comparisons were made using two-tailed t-tests. Significant differences were as follows: MCF-7 wtBRCA1 vs control, P<0.001 at 100–400 μM I3C; MCF-7 BRCA1-siRNA vs control, P<0.001 at 200–500 μM I3C; T47D wtBRCA1 vs control, P<0.001 at 100–500 μM I3C; T47D BRCA1-siRNA vs control, P<0.001 at 200–500 μM I3C; DU-145 wtBRCA1 vs control, P<0.001 at 100–400 μM I3C; DU-145 BRCA1-siRNA vs control, P<0.001 at 100–500 μM I3C; DU-145 wtBRCA1 vs control, P<0.001, 100–400 μM I3C; and DU-145 BRCA2-siRNA vs control, P<0.001 at 200–500 μM I3C.
Figure 6
Figure 6
Contribution of BRCA genes to regulation of ER-α and AR activity by I3C and genistein. (A) Rescue of I3C inhibition of E2-stimulated ER-α activity by BRCA1-siRNA. MCF-7 cells were pretreated with BRCA1-siRNA, BRCA2-siRNA, control-siRNA (50 nM × 72 h), or no siRNA (vehicle only). After the first 48 h of siRNA treatment, they were transfected with the ERE-TK-Luc reporter overnight, washed, postincubated±17β-estradiol (E2, 1 μM) and ±I3C (100 μM) for 24 h, and tested for luciferase activity. Values are expressed relative to the +E2 positive control (no siRNA, no I3C) and are means±s.e.m.'s of three independent experiments. In each experiment, each assay condition was tested in four replicate wells, and the values were averaged. BRCA1 (but not BRCA2 or control) siRNA reversed the inhibition of E2-stimulated ER-α activity by I3C (P<0.001). (B) Rescue of genistein inhibition of E2-stimulated ER-α activity by BRCA1-siRNA. The experiment was performed as described above, except that the cells were treated ±genistein (5 μM) instead of I3C. Luciferase values are expressed relative to the +E2 positive control (no siRNA, no genistein) and are means±s.e.m.'s of three independent experiments, with each assay condition tested in four replicate wells per experiment. BRCA1 (but not BRCA2 or control) siRNA reversed the inhibition of E2-stimulated ER-α activity by genistein (P<0.001). (C, D) Contribution of BRCA1 to inhibition of DHT-stimulated AR activity by I3C and genistein. LNCaP (C) or PC-3 (D) cells were pretreated with BRCA1-siRNA, control-siRNA (50 nM × 72 h), or no siRNA. LNCaP cells, which are AR-positive, were transfected with an androgen-responsive reporter (ARE-TK-Luc); while PC-3 cells, which are AR-negative, were cotransfected with an AR expression vector plus ARE-TK-Luc. The cells were treated with dihydrotestosterone (DHT, 10 nM), I3C (25 μM), and/or genistein (1.0 μM) for 24 h and assayed for luciferase activity. BRCA1-siRNA enhanced DHT-stimulated AR activity and partially rescued the inhibition of AR activity by I3C and genistein (left panels). The asterisks indicate a significant comparison (P<0.01). (E) Effect of BRCA1-siRNA and phytochemicals on AR protein levels in LNCaP cells. Cells were pretreated with BRCA1 or control siRNA and then treated with I3C, genistein, or DHT as described in (C). The cells were then harvested and Western blotted for AR or actin. (F) Effect of BRCA1-siRNA on AR mRNA levels. LNCaP cells were pretreated with BRCA1- or control-siRNA, treated with DHT for 24 h, and harvested for semiquantitative RT–PCR to detect BRCA1, AR, or β-actin.
Figure 7
Figure 7
Thapsigargin and tunicamycin upregulate BRCA gene expression. (A, B) Dose–response for induction of BRCA mRNAs by thapsigargin in T47D (A) and MCF-7 (B) cells. Subconfluent proliferating cells were incubated with the indicated doses of thapsigargin for 24-h and then harvested for semiquantitative RT–PCR analysis of BRCA1, BRCA2, and β-actin (control gene). (C) Time course for induction of BRCA1 mRNAs by thapsigargin in MCF-7 cells. MCF-7 cells were incubated with thapsigargin (300 nM) for different time intervals up to 48-h and then harvested for semiquantitative RT–PCR analysis of BRCA1, BRCA2, and β-actin. (D, E) Dose–response for induction of BRCA1 protein by thapsigargin in T47D (D) and MCF-7 (E) cells. Cells were incubated with the indicated doses of thapsigargin for 24-h and then harvested for Western blotting to detect BRCA1 and actin (control for loading and transfer). (F, G) Dose–response for induction of BRCA proteins by tunicamycin in T47D (F) and MCF-7 (G) cells. Cells were incubated with the indicated doses of thapsigargin for 24-h and then harvested for Western blotting to detect BRCA1, BRCA2, and actin.
Figure 8
Figure 8
Induction of BRCA expression by I3C requires the kinase PERK (EIFAK3). (A) Dominant negative (DN) PERK blocks I3C induction of BRCA protein. Subconfluent proliferating MCF-7 cells were transfected overnight with control (vehicle only), empty pcDNA3 vector, or DN-PERK (15-μg plasmid DNA per 100-mm dish) using Lipofectamine™. The transfected cells were washed, allowed to recover for several hours, treated±I3C for 24-h, and harvested for Western blotting to detect BRCA1, BRCA2, or actin (control for loading and transfer). (B) Dominant negative IRE1 fails to block I3C induction of BRCA protein. Assays were performed as described in (A), except using DN-IRE1 instead of DN-PERK. (C) Dominant negative ATF4 fails to block I3C induction of BRCA protein. Assays were performed as described in (A), except using DN-ATF4 instead of DN-PERK.
Figure 9
Figure 9
Stimulation of endoplasmic reticulum stress signalling by I3C, genistein, and BRCA1. (A) Stimulation of ERSE-driven reporter activity by I3C and tunicamycin. MCF-7 or T47D cells were transfected overnight with the indicated luciferase reporter, washed, postincubated with tunicamycin (1 μg/ml) and/or I3C (100 μM) for 24-h, and harvested for luciferase assays. Luciferase activity was expressed relative to that observed using the ERSEwt-Luc reporter in the absence of tunicamycin or I3C. Values are means±s.e.m.'s of four replicate wells. The reporters tested were driven by the wt endoplasmic reticulum stress-response element (ERSEwt-Luc), a mutant ERSE (ERSEmut-Luc), and three copies of the ERSE-II element (ERSEII3x-Luc). (B) Stimulation of ERSE reporter activity by genistein. Assays were performed as above, except that after transfection of reporters, the cells were treated with genistein (0.5 or 1.0 μM) for 24 h. (C) Stimulation of CHOP promoter–reporter activity by I3C and gensitein. Cells were transfected overnight with the a reporter composed of the CHOP promoter upstream of a luciferase gene (pCHOP-Luc), washed, and postincubated with different doses of I3C or genistein for 24 h. Luciferase activity was expressed relative to that in the absence of I3C or genistein. The values are means±s.e.m.'s of four replicate wells. (D) Dependence of basal ERSE reporter activity on endogenous BRCA1. Proliferating cells were pretreated with BRCA1-siRNA, control-siRNA (50 nM × 72-h), or no siRNA (vehicle only). After 48 h of siRNA treatment, they were transfected with the indicated ERSE reporter. After siRNA treatment and transfection, the cells were washed, postincubated for 24 h, and harvested for luciferase assays. Values are expressed relative to the ERSEwt-Luc control (no siRNA) and are means±s.e.m.'s of four replicate wells. (E) Stimulation of ERSE reporter activity by wtBRCA1. Cells were cotransfected overnight with wtBRCA1, empty pcDNA3 vector, or no vector (vehicle only) and the indicated reporter. The cells were washed and postincubated for 24 h. Luciferase values are expressed relative to the ERSEwt-Luc reporter in the absence of wtBRCA1 or pcDNA3 and are means±s.e.m.' of quadruplicate wells. (F) Dependence of I3C-stimulated ERSE activity on endogenous BRCA1. Assays were performed as described in (D), except that after siRNA treatment and transfection, the cells were postincubated for 24 h in the absence or presence of I3C (100 μM). (G) Dependence of genistein-stimulated ERSE activity on endogenous BRCA1. Assays were performed as described in (F), except using genistein (1 μM) instead of I3C.
Figure 9
Figure 9
Stimulation of endoplasmic reticulum stress signalling by I3C, genistein, and BRCA1. (A) Stimulation of ERSE-driven reporter activity by I3C and tunicamycin. MCF-7 or T47D cells were transfected overnight with the indicated luciferase reporter, washed, postincubated with tunicamycin (1 μg/ml) and/or I3C (100 μM) for 24-h, and harvested for luciferase assays. Luciferase activity was expressed relative to that observed using the ERSEwt-Luc reporter in the absence of tunicamycin or I3C. Values are means±s.e.m.'s of four replicate wells. The reporters tested were driven by the wt endoplasmic reticulum stress-response element (ERSEwt-Luc), a mutant ERSE (ERSEmut-Luc), and three copies of the ERSE-II element (ERSEII3x-Luc). (B) Stimulation of ERSE reporter activity by genistein. Assays were performed as above, except that after transfection of reporters, the cells were treated with genistein (0.5 or 1.0 μM) for 24 h. (C) Stimulation of CHOP promoter–reporter activity by I3C and gensitein. Cells were transfected overnight with the a reporter composed of the CHOP promoter upstream of a luciferase gene (pCHOP-Luc), washed, and postincubated with different doses of I3C or genistein for 24 h. Luciferase activity was expressed relative to that in the absence of I3C or genistein. The values are means±s.e.m.'s of four replicate wells. (D) Dependence of basal ERSE reporter activity on endogenous BRCA1. Proliferating cells were pretreated with BRCA1-siRNA, control-siRNA (50 nM × 72-h), or no siRNA (vehicle only). After 48 h of siRNA treatment, they were transfected with the indicated ERSE reporter. After siRNA treatment and transfection, the cells were washed, postincubated for 24 h, and harvested for luciferase assays. Values are expressed relative to the ERSEwt-Luc control (no siRNA) and are means±s.e.m.'s of four replicate wells. (E) Stimulation of ERSE reporter activity by wtBRCA1. Cells were cotransfected overnight with wtBRCA1, empty pcDNA3 vector, or no vector (vehicle only) and the indicated reporter. The cells were washed and postincubated for 24 h. Luciferase values are expressed relative to the ERSEwt-Luc reporter in the absence of wtBRCA1 or pcDNA3 and are means±s.e.m.' of quadruplicate wells. (F) Dependence of I3C-stimulated ERSE activity on endogenous BRCA1. Assays were performed as described in (D), except that after siRNA treatment and transfection, the cells were postincubated for 24 h in the absence or presence of I3C (100 μM). (G) Dependence of genistein-stimulated ERSE activity on endogenous BRCA1. Assays were performed as described in (F), except using genistein (1 μM) instead of I3C.

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