Limits...
The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer.

Yin YD, Fu M, Brooke DG, Heinrich DM, Denny WA, Jamieson SM - Front Oncol (2014)

Bottom Line: AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression.SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines.These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Auckland , New Zealand.

ABSTRACT
AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

No MeSH data available.


Related in: MedlinePlus

AKR1C3 mRNA expression is upregulated in tumor samples from CRPC patients but downregulated in breast cancer patient tumors. (A) Meta-analysis of AKR1C3 mRNA expression in normal prostate (n = 54), primary prostate carcinoma (n = 133), and CRPC (n = 100) tissue in patients from seven Oncomine prostate cancer datasets. The upper dotted line indicates 75th percentile for CRPC. (B) Correlation of NQO1 mRNA expression with AKR1C3 mRNA expression in CRPC patients from (A). (C) Meta-analysis of AKR1C3 mRNA expression in normal breast (Normal, n = 257), premenopausal ER-positive breast cancer (ER+ pre, n = 281), post-menopausal ER-positive breast cancer (ER+ post, n = 1337), premenopausal ER-negative breast cancer (ER− pre, n = 189), and post-menopausal ER-negative breast cancer (ER− post, n = 278) patients in seven Oncomine breast cancer datasets. The line in each box represents the median, the lower, and upper boundaries represent the 25th and 75th percentiles, and the whiskers show the 5th and 95th percentiles. (D)AKR1C3 mRNA expression in paired normal and ER-positive breast cancer samples in post-menopausal women (n = 23) from (C). Significance of differences was evaluated by one-way ANOVA with Dunnett’s multiple comparison analysis (A,C) or by Student’s t-test (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4061482&req=5

Figure 2: AKR1C3 mRNA expression is upregulated in tumor samples from CRPC patients but downregulated in breast cancer patient tumors. (A) Meta-analysis of AKR1C3 mRNA expression in normal prostate (n = 54), primary prostate carcinoma (n = 133), and CRPC (n = 100) tissue in patients from seven Oncomine prostate cancer datasets. The upper dotted line indicates 75th percentile for CRPC. (B) Correlation of NQO1 mRNA expression with AKR1C3 mRNA expression in CRPC patients from (A). (C) Meta-analysis of AKR1C3 mRNA expression in normal breast (Normal, n = 257), premenopausal ER-positive breast cancer (ER+ pre, n = 281), post-menopausal ER-positive breast cancer (ER+ post, n = 1337), premenopausal ER-negative breast cancer (ER− pre, n = 189), and post-menopausal ER-negative breast cancer (ER− post, n = 278) patients in seven Oncomine breast cancer datasets. The line in each box represents the median, the lower, and upper boundaries represent the 25th and 75th percentiles, and the whiskers show the 5th and 95th percentiles. (D)AKR1C3 mRNA expression in paired normal and ER-positive breast cancer samples in post-menopausal women (n = 23) from (C). Significance of differences was evaluated by one-way ANOVA with Dunnett’s multiple comparison analysis (A,C) or by Student’s t-test (D).

Mentions: We analyzed the online microarray database Oncomine to determine the AKR1C3 mRNA expression levels in CRPC and breast cancer patients relative to normal tissue or primary disease. Meta-analysis of seven prostate cancer datasets that included normal prostate or primary prostate carcinoma samples in addition to CRPC revealed that AKR1C3 expression is significantly upregulated in CRPC relative to both normal prostate and primary prostate carcinoma (P < 0.001; one-way ANOVA with Dunnett’s multiple comparison analysis; Figure 2A). The magnitude of this difference was most evident in the highest AKR1C3-expressing samples, where the upper quartile of CRPC corresponded to the 97th percentile of primary prostate carcinoma and above the 100th percentile for normal prostate. Since AKR1C3 is regulated by Nrf2 (32), we also analyzed the samples for mRNA expression of NQO1, a reporter of Nrf2 activity (42, 43), to determine if the upregulation of AKR1C3 in CRPC samples was driven by increased Nrf2 activity. NQO1 mRNA levels were unchanged in CRPC relative to normal prostate or primary prostate carcinoma (data not shown) and there was no significant correlation between NQO1 mRNA and AKR1C3 mRNA expression in CRPC patients (R2 = 0.02; Pearson product-moment correlation; Figure 2B). A similar meta-analysis was conducted across seven breast cancer datasets that included normal breast samples, showing that AKR1C3 mRNA expression is significantly downregulated in breast cancer samples relative to normal breast tissue (P < 0.001; one-way ANOVA with Dunnett’s multiple comparison analysis; Figure 2C), including in paired samples from post-menopausal ER-positive breast cancer patients (P < 0.0001) (Figure 2D).


The Activity of SN33638, an Inhibitor of AKR1C3, on Testosterone and 17β-Estradiol Production and Function in Castration-Resistant Prostate Cancer and ER-Positive Breast Cancer.

Yin YD, Fu M, Brooke DG, Heinrich DM, Denny WA, Jamieson SM - Front Oncol (2014)

AKR1C3 mRNA expression is upregulated in tumor samples from CRPC patients but downregulated in breast cancer patient tumors. (A) Meta-analysis of AKR1C3 mRNA expression in normal prostate (n = 54), primary prostate carcinoma (n = 133), and CRPC (n = 100) tissue in patients from seven Oncomine prostate cancer datasets. The upper dotted line indicates 75th percentile for CRPC. (B) Correlation of NQO1 mRNA expression with AKR1C3 mRNA expression in CRPC patients from (A). (C) Meta-analysis of AKR1C3 mRNA expression in normal breast (Normal, n = 257), premenopausal ER-positive breast cancer (ER+ pre, n = 281), post-menopausal ER-positive breast cancer (ER+ post, n = 1337), premenopausal ER-negative breast cancer (ER− pre, n = 189), and post-menopausal ER-negative breast cancer (ER− post, n = 278) patients in seven Oncomine breast cancer datasets. The line in each box represents the median, the lower, and upper boundaries represent the 25th and 75th percentiles, and the whiskers show the 5th and 95th percentiles. (D)AKR1C3 mRNA expression in paired normal and ER-positive breast cancer samples in post-menopausal women (n = 23) from (C). Significance of differences was evaluated by one-way ANOVA with Dunnett’s multiple comparison analysis (A,C) or by Student’s t-test (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4061482&req=5

Figure 2: AKR1C3 mRNA expression is upregulated in tumor samples from CRPC patients but downregulated in breast cancer patient tumors. (A) Meta-analysis of AKR1C3 mRNA expression in normal prostate (n = 54), primary prostate carcinoma (n = 133), and CRPC (n = 100) tissue in patients from seven Oncomine prostate cancer datasets. The upper dotted line indicates 75th percentile for CRPC. (B) Correlation of NQO1 mRNA expression with AKR1C3 mRNA expression in CRPC patients from (A). (C) Meta-analysis of AKR1C3 mRNA expression in normal breast (Normal, n = 257), premenopausal ER-positive breast cancer (ER+ pre, n = 281), post-menopausal ER-positive breast cancer (ER+ post, n = 1337), premenopausal ER-negative breast cancer (ER− pre, n = 189), and post-menopausal ER-negative breast cancer (ER− post, n = 278) patients in seven Oncomine breast cancer datasets. The line in each box represents the median, the lower, and upper boundaries represent the 25th and 75th percentiles, and the whiskers show the 5th and 95th percentiles. (D)AKR1C3 mRNA expression in paired normal and ER-positive breast cancer samples in post-menopausal women (n = 23) from (C). Significance of differences was evaluated by one-way ANOVA with Dunnett’s multiple comparison analysis (A,C) or by Student’s t-test (D).
Mentions: We analyzed the online microarray database Oncomine to determine the AKR1C3 mRNA expression levels in CRPC and breast cancer patients relative to normal tissue or primary disease. Meta-analysis of seven prostate cancer datasets that included normal prostate or primary prostate carcinoma samples in addition to CRPC revealed that AKR1C3 expression is significantly upregulated in CRPC relative to both normal prostate and primary prostate carcinoma (P < 0.001; one-way ANOVA with Dunnett’s multiple comparison analysis; Figure 2A). The magnitude of this difference was most evident in the highest AKR1C3-expressing samples, where the upper quartile of CRPC corresponded to the 97th percentile of primary prostate carcinoma and above the 100th percentile for normal prostate. Since AKR1C3 is regulated by Nrf2 (32), we also analyzed the samples for mRNA expression of NQO1, a reporter of Nrf2 activity (42, 43), to determine if the upregulation of AKR1C3 in CRPC samples was driven by increased Nrf2 activity. NQO1 mRNA levels were unchanged in CRPC relative to normal prostate or primary prostate carcinoma (data not shown) and there was no significant correlation between NQO1 mRNA and AKR1C3 mRNA expression in CRPC patients (R2 = 0.02; Pearson product-moment correlation; Figure 2B). A similar meta-analysis was conducted across seven breast cancer datasets that included normal breast samples, showing that AKR1C3 mRNA expression is significantly downregulated in breast cancer samples relative to normal breast tissue (P < 0.001; one-way ANOVA with Dunnett’s multiple comparison analysis; Figure 2C), including in paired samples from post-menopausal ER-positive breast cancer patients (P < 0.0001) (Figure 2D).

Bottom Line: AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression.SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines.These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

View Article: PubMed Central - PubMed

Affiliation: Auckland Cancer Society Research Centre, The University of Auckland , Auckland , New Zealand.

ABSTRACT
AKR1C3 is a novel therapeutic target in castration-resistant prostate cancer (CRPC) and estrogen receptor (ER)-positive breast cancer because of its ability to produce testosterone and 17β-estradiol intratumorally, thus promoting nuclear receptor signaling and tumor progression. A panel of CRPC, ER-positive breast cancer and high/low AKR1C3-expressing cell lines were treated with SN33638, a selective inhibitor of AKR1C3, in the presence of hormone or prostaglandin (PG) precursors, prior to evaluation of cell proliferation and levels of 11β-PG F2α (11β-PGF2α), testosterone, 17β-estradiol, and prostate-specific antigen (PSA). A meta-analysis of AKR1C3 mRNA expression in patient samples was also conducted, which revealed that AKR1C3 mRNA was upregulated in CRPC, but downregulated in ER-positive breast cancer. 11β-PGF2α and testosterone levels in the cell line panel correlated with AKR1C3 protein expression. SN33638 prevented 11β-PGF2α formation in cell lines that expressed AKR1C3, but partially inhibited testosterone formation and subsequently cell proliferation and/or PSA expression only in high (LAPC4 AKR1C3-overexpressing cells) or moderate (22RV1) AKR1C3-expressing cell lines. SN33638 had little effect on 17β-estradiol production or estrone-stimulated cell proliferation in ER-positive breast cancer cell lines. Although SN33638 could prevent 11β-PGF2α formation, its ability to prevent testosterone and 17β-estradiol production and their roles in CRPC and ER-positive breast cancer progression was limited due to AKR1C3-independent steroid hormone production, except in LAPC4 AKR1C3 cells where the majority of testosterone was AKR1C3-dependent. These results suggest that inhibition of AKR1C3 is unlikely to produce therapeutic benefit in CRPC and ER-positive breast cancer patients, except possibly in the small subpopulation of CRPC patients with tumors that have upregulated AKR1C3 expression and are dependent on AKR1C3 to produce the testosterone required for their growth.

No MeSH data available.


Related in: MedlinePlus