Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer
Abstract
1. Introduction
2. Materials and Methods
2.1. Cell Culture
2.2. Tissue Samples
2.3. MicroRNA Isolation
2.4. MiRNA Reverse Transcription and Real-Time PCR (RT-PCR)
2.5. Bioinformatics Analysis
2.6. Statistical Analysis
3. Results
3.1. Selection of Estradiol-, Progesterone-, Testosterone-Sensitive miRNAs
3.2. Analysis of the Hormone-Sensitive MiRNAs Expression in Breast Cancer
3.3. Expression of MiR-190a, MiR-190b, MiR-27a, MiR-193b, MiR-324, MiR-423, MiR-200b, and MiR-21 in Relation to Clinicopathologic Features of ER- and/or PR-Positive BC
3.4. Expression of MiR-190a, MiR-190b, MiR-27a, MiR-193b, MiR-324, MiR-423, MiR-200b, and MiR-21 in Relation to Clinicopathologic Features of ER- and PR-Negative BC
4. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Characteristics | ER- and/or PR-Positive (n = 156) | ER- and PR-Negative (n = 40) | |
---|---|---|---|
Age (mean and range, year) | 61 (27–90) | 55 (38–76) | |
T stage | T1 | 71 | 18 |
T2 | 81 | 20 | |
T3 | 2 | 1 | |
T4 | 2 | 1 | |
N stage | N0 | 103 | 27 |
N1 | 37 | 7 | |
N2 | 11 | 6 | |
N3 | 5 | - | |
ER score | 0–2 | 3 | 40 |
3–5 | 7 | - | |
6–8 | 146 | - | |
PR score | 0–2 | 25 | 40 |
3–5 | 34 | - | |
6–8 | 97 | - | |
HER2 score | 0 | 72 | 18 |
1 | 47 | 5 | |
2–3 | 37 | 17 |
miRNA | ESR1 and ESR2 Binding Sites in Promoter According to ChipSeq Data (Homo Sapiens) [13] | ESR1 and ESR2 Binding Sites in Promoter According to Position Weight Matrix (Homo Sapiens) [13] | ESR1 and ESR2 Binding Sites in Promoter According to Position Weight Matrix (Mus Musculus and Rattus Norvegicus) [13] | AR/PR Binding Sites in Promoter According to Position Weight Matrix (Homo Sapiens) | AR/PR Binding Sites in Promoter According to Position Weight Matrix (Rattus Norvegicus) | Comments |
---|---|---|---|---|---|---|
hsa-mir-21 | + | + | only mouse | + | + | It was demonstrated that androgen induced AR binding to the miR-21 promoter; MiR-21 expression was induced by R1881 in LNCaP and LAPC-4 cells [19]. Mibolerone inhibited basal expression of miR-21 in MCF-7 breast cancer cells [20]. Estradiol inhibited miR-21 expression in MCF-7 cells [21]. |
hsa-mir-190b | + | + | + | + | - | MiR-190b is the highest up-regulated miRNA in ER+ breast cancers compared to ER− tumors. Did not observe an increase of miR-190b expression levels in MCF-7 or in T-47D treated by estradiol (1 nM for MCF-7 and 10 nM for T-47D, 6 h, 18 h, and 4 days) [22]. |
hsa-mir-200a/ hsa-mir-200b/ hsa-mir-429 | + | + | + | - | - | MiR-200b showed the highest fold change under the influence of R1881 among androgen-sensitive miRNAs (PC3-AR cells) [23]. MiR-200b expression in MCF-7 cells decreased after 6 h of incubation with 10 nM estradiol [24]. |
hsa-mir-23a/ hsa-mir-24-2/ hsa-mir-27a | + | - | + | - | - | AR is able to associate transiently with the miR-23a/27a/24-2 promoter in response to androgen to initiate cluster transcription. The highest-fold change was observed for miR-27a and miR-23a (LNCaP cells treated with mibolerone) [25]. Estrogen induced miR-23a expression in SNU-387 cells [26]. |
hsa-mir-342 | + | - | + | + | - | MiR-342 expression is positively correlated with ERα mRNA expression in human BC [27]. |
hsa-mir-190a | - | - | - | + | + | The promoter region of miR-190a contains half of an estrogen response element. ERα binds directly to this promoter [28]. Androgen inhibits miR-190a expression through direct binding to the half-site of ARE in miR-190a promoter (LNCaP cells) [29]. |
hsa-mir-378a | - | + | + | + | + | |
hsa-mir-324 | - | + | + | + | + | |
hsa-mir-423 | - | + | only rat | + | + | |
hsa-mir-149 | - | + | only rat | + | + | |
hsa-mir-365b | + | + | only rat | + | - | |
hsa-mir-574 | + | - | only mouse | + | - | |
hsa-mir-30a | + | - | only mouse | + | - | AR does not target the miR-30a promoter; AR activating signal may indirectly downregulate miR-30a (MDA-MB-453 cells) [30]. |
hsa-mir-10a | + | + | + | - | - | |
hsa-mir-483 | + | + | + | - | - | |
hsa-let-7a-3/ hsa-let-7b | + | - | + | - | - | |
hsa-mir-196a-2 | + | + | - | - | - | MiR-196a expression is regulated by the estrogen receptor [31]. |
hsa-mir-33b | + | - | - | - | - | |
hsa-miR-193b | - | + | + | + | - | Targets ER [32]. |
hsa-miR-126 | - | + | + | + | - | Targets PR (regulation confirmed using mouse mammary epithelial cells) [33]. |
miRNA | Time, h | Relative Level of miRNA | |||||
---|---|---|---|---|---|---|---|
Estradiol | Testosterone | Progesterone | |||||
10 nM | 100 nM | 10 nM | 100 nM | 10 nM | 100 nM | ||
miR-23a | 6 | 1.12 | 1.08 | 0.96 | 0.86 | 0.84 | 0.84 |
24 | 0.89 | 0.95 | 0.88 | 1.00 | 0.92 | 0.88 | |
48 | 0.89 | 0.85 | 1.02 | 0.94 | 1.11 | 0.92 | |
miR-27a | 6 | 1.12 | 0.88 | 0.92 | 0.76 * | 0.89 | 0.93 |
24 | 1.07 | 1.10 | 1.09 | 1.08 | 0.93 | 0.92 | |
48 | 0.92 | 0.95 | 1.13 | 1.09 | 1.01 | 1.16 | |
miR-190b | 6 | 0.97 | 0.75 ** | 0.96 | 0.92 | 0.93 | 1.10 |
24 | 1.35 * | 1.37 ** | 1.13 | 1.09 | 1.02 | 1.03 | |
48 | 1.12 | 1.09 | 1.05 | 1.15 | 1.14 | 1.29 * | |
miR-190a | 6 | 1.05 | 1.01 | 0.91 | 0.88 | 1.01 | 0.90 |
24 | 1.09 | 1.02 | 0.90 | 0.99 | 0.79 | 0.75 * | |
48 | 1.08 | 1.17 | 1.24 * | 1.38 * | 0.90 | 0.96 | |
miR-200b | 6 | 1.01 | 0.79 ** | 1.00 | 0.88 | 1.02 | 0.98 |
24 | 0.98 | 1.01 | 1.10 | 0.99 | 0.91 | 0.96 | |
48 | 1.01 | 1.11 | 1.24 * | 1.32 ** | 0.95 | 1.07 | |
miR-21 | 6 | 1.03 | 0.98 | 0.92 | 0.62 ** | 1.17 | 1.36 * |
24 | 0.97 | 0.98 | 0.89 | 0.91 | 0.92 | 0.90 | |
48 | 1.07 | 1.08 | 1.36 ** | 1.40 ** | 1.11 | 1.08 | |
miR-126 | 6 | 1.01 | 1.03 | 0.90 | 1.05 | 0.87 | 0.95 |
24 | 0.94 | 0.88 | 1.06 | 0.94 | 1.01 | 1.12 | |
48 | 1.13 | 1.11 | 1.18 | 0.99 | 0.93 | 1.07 | |
miR-378 | 6 | 1.09 | 1.00 | 0.88 | 0.94 | 0.90 | 1.08 |
24 | 1.05 | 1.05 | 1.11 | 0.97 | 0.95 | 1.04 | |
48 | 1.00 | 1.17 | 1.15 | 1.19 | 0.94 | 1.12 | |
miR-423 | 6 | 0.98 | 0.90 | 0.89 | 0.93 | 0.91 | 1.09 |
24 | 1.04 | 1.06 | 0.99 | 0.87 | 0.96 | 0.99 | |
48 | 0.97 | 0.99 | 1.50 ** | 1.42 ** | 0.90 | 0.97 | |
miR-149 | 6 | 1.25 | 1.01 | 0.95 | 0.91 | 0.96 | 1.06 |
24 | 0.98 | 0.94 | 0.99 | 0.95 | 0.90 | 0.94 | |
48 | 0.89 | 1.05 | 1.05 | 0.89 | 1.02 | 1.18 | |
miR-193b | 6 | 1.07 | 1.00 | 0.93 | 0.95 | 0.92 | 1.07 |
24 | 1.02 | 1.10 | 1.05 | 1.08 | 1.00 | 0.89 | |
48 | 1.24 | 1.30 ** | 1.30 ** | 1.40 ** | 1.07 | 1.08 | |
miR-324 | 6 | 1.35 * | 1.21 | 0.91 | 0.95 | 1.61 ** | 2.20 ** |
24 | 0.99 | 1.06 | 1.06 | 1.05 | 1.05 | 1.04 | |
48 | 1.08 | 1.07 | 1.15 | 1.33 ** | 0.94 | 1.09 | |
miR-342 | 6 | 0.83 | 0.96 | 0.89 | 1.10 | 0.92 | 1.12 |
24 | 0.96 | 1.02 | 1.15 | 1.10 | 0.89 | 0.94 | |
48 | 1.07 | 1.08 | 1.17 | 1.19 | 0.90 | 1.18 |
Characteristics | n | Relative Level * of miRNA and p-Value | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
miR-190a | p-Value | miR-190b | p-Value | miR-27a | p-Value | miR-193b | p-Value | |||
ER and PR status | ER+ and/or PR+ | 156 | 0.10 | 0.165 | 4.84 | <0.001 | 0.33 | 0.443 | 0.58 | 0.168 |
ER− and PR− | 40 | 0.33 | 1.13 | 0.44 | 0.36 | |||||
HER2 status | HER2+ | 52 | 0.10 | 0.728 | 3.86 | 0.985 | 0.34 | 0.388 | 0.72 | 0.193 |
HER2− | 144 | 0.12 | 3.76 | 0.39 | 0.47 | |||||
Ki-67 index (%) | <14 | 65 | 0.11 | 0.753 | 3.89 | 0.941 | 0.49 | 0.394 | 0.49 | 0.567 |
≥14 | 131 | 0.11 | 3.64 | 0.35 | 0.53 | |||||
Age | ≤50 | 48 | 0.21 | 0.107 | 2.79 | 0.119 | 0.48 | 0.045 | 0.56 | 0.861 |
>50 | 148 | 0.11 | 4.26 | 0.33 | 0.52 | |||||
N stage | N0 | 130 | 0.17 | 0.103 | 3.47 | 0.592 | 0.37 | 0.834 | 0.65 | 0.022 |
N1-N3 | 66 | 0.09 | 4.21 | 0.42 | 0.37 | |||||
miR-324 | p-Value | miR-423 | p-Value | miR-200b | p-Value | miR-21 | p-Value | |||
ER and PR status | ER+ and/or PR+ | 156 | 0.48 | 0.129 | 0.65 | 0.800 | 1.77 | 0.676 | 1.78 | 0.004 |
ER− and PR− | 40 | 0.68 | 0.74 | 1.53 | 3.48 | |||||
HER2 status | HER2+ | 52 | 0.60 | 0.180 | 0.80 | 0.004 | 2.99 | 0.024 | 1.62 | 0.342 |
HER2− | 144 | 0.47 | 0.55 | 1.46 | 1.95 | |||||
Ki-67 index (%) | <14 | 65 | 0.39 | 0.257 | 0.56 | 0.038 | 1.26 | 0.030 | 2.02 | 0.947 |
≥14 | 131 | 0.60 | 0.71 | 2.04 | 1.88 | |||||
Age | ≤50 | 48 | 0.60 | 0.103 | 0.69 | 0.958 | 1.68 | 0.598 | 3.52 | 0.003 |
>50 | 148 | 0.48 | 0.65 | 1.50 | 1.68 | |||||
N stage | N0 | 130 | 0.55 | 0.210 | 0.68 | 0.068 | 1.51 | 0.491 | 1.84 | 0.445 |
N1-N3 | 66 | 0.48 | 0.52 | 1.78 | 2.13 |
Characteristics | n | Relative Level * of miRNA and p-Value | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
miR-190a | p-Value | miR-190b | p-Value | miR-27a | p-Value | miR-193b | p-Value | |||
ER+ and/or PR+ | ||||||||||
T stage | T1 | 71 | 0.11 | 0.783 | 4.80 | 0.995 | 0.30 | 0.248 | 0.43 | 0.070 |
T2–T4 | 85 | 0.09 | 4.93 | 0.46 | 0.74 | |||||
N stage | N0 | 103 | 0.13 | 0.058 | 4.57 | 0.477 | 0.37 | 0.391 | 0.69 | 0.013 |
N1–N3 | 53 | 0.08 | 5.41 | 0.52 | 0.38 | |||||
Ki-67 index (%) | <M ** | 81 | 0.17 | 0.071 | 4.59 | 0.231 | 0.47 | 0.261 | 0.56 | 0.316 |
≥M ** | 75 | 0.09 | 5.42 | 0.32 | 0.66 | |||||
ER score | 6–8 | 146 | 0.09 | 0.475 | 5.04 | 0.078 | 0.32 | 0.113 | 0.54 | 0.013 |
0–5 | 10 | 0.19 | 2.12 | 0.52 | 1.74 | |||||
PR score | 6–8 | 97 | 0.09 | 0.004 | 4.71 | 0.840 | 0.29 | 0.048 | 0.49 | 0.258 |
0–5 | 59 | 0.21 | 6.41 | 0.49 | 0.81 | |||||
Age | ≤50 | 30 | 0.12 | 0.226 | 5.41 | 0.893 | 0.48 | 0.227 | 0.90 | 0.360 |
>50 | 126 | 0.10 | 4.80 | 0.31 | 0.55 | |||||
miR-324 | p-Value | miR-423 | p-Value | miR-200b | p-Value | miR-21 | p-Value | |||
ER+ and/or PR+ | ||||||||||
T stage | T1 | 71 | 0.43 | 0.216 | 0.59 | 0.290 | 2.09 | 0.109 | 1.68 | 0.247 |
T2–T4 | 85 | 0.50 | 0.67 | 1.36 | 1.81 | |||||
N stage | N0 | 103 | 0.53 | 0.313 | 0.68 | 0.039 | 1.64 | 0.832 | 1.74 | 0.802 |
N1–N3 | 53 | 0.46 | 0.49 | 1.77 | 1.95 | |||||
Ki-67 index (%) | <M ** | 81 | 0.44 | 0.694 | 0.57 | 0.055 | 1.53 | 0.253 | 1.84 | 0.494 |
≥M ** | 75 | 0.49 | 0.68 | 2.04 | 1.69 | |||||
ER score | 6–8 | 146 | 0.48 | 0.467 | 0.62 | 0.756 | 1.88 | 0.006 | 1.69 | 0.106 |
0–5 | 10 | 0.89 | 0.88 | 0.28 | 2.09 | |||||
PR score | 6–8 | 97 | 0.45 | 0.211 | 0.63 | 0.600 | 1.85 | 0.858 | 1.76 | 0.336 |
0–5 | 59 | 0.61 | 0.65 | 1.50 | 1.83 | |||||
Age | ≤50 | 30 | 0.57 | 0.232 | 0.71 | 0.741 | 1.72 | 0.729 | 2.28 | 0.085 |
>50 | 126 | 0.46 | 0.62 | 1.73 | 1.65 |
Characteristics | n | Relative Level * of miRNA and p-Value | ||||||||
---|---|---|---|---|---|---|---|---|---|---|
miR-190a | p-Value | miR-190b | p-Value | miR-27a | p-Value | miR-193b | p-Value | |||
T stage | T1 | 18 | 0.33 | 0.372 | 0.90 | 0.629 | 0.40 | 0.240 | 0.57 | 0.176 |
T2–T4 | 22 | 0.37 | 1.26 | 0.57 | 0.35 | |||||
N stage | N0 | 27 | 0.37 | 0.824 | 1.07 | 0.835 | 0.39 | 0.183 | 0.44 | 0.725 |
N1–N3 | 13 | 0.24 | 1.14 | 0.52 | 0.35 | |||||
Ki-67 index (%) | ≤M ** | 19 | 0.39 | 0.162 | 1.45 | 0.191 | 0.45 | 0.779 | 0.47 | 0.272 |
>M ** | 21 | 0.08 | 1.02 | 0.44 | 0.35 | |||||
Age | ≤50 | 18 | 0.34 | 0.228 | 0.64 | 0.275 | 0.55 | 0.091 | 0.37 | 0.617 |
>50 | 22 | 0.26 | 1.24 | 0.39 | 0.43 | |||||
miR-324 | p-Value | miR-423 | p-Value | miR-200b | p-Value | miR-21 | p-Value | |||
T stage | T1 | 18 | 0.65 | 0.987 | 0.80 | 0.729 | 1.11 | 0.036 | 3.87 | 0.703 |
T2–T4 | 26 | 0.75 | 0.51 | 2.04 | 3.47 | |||||
N stage | N0 | 27 | 0.69 | 0.391 | 0.70 | 0.969 | 1.33 | 0.349 | 3.33 | 0.101 |
N1–N3 | 13 | 0.62 | 0.80 | 2.04 | 6.68 | |||||
Ki-67 index (%) | ≤M ** | 19 | 0.89 | 0.101 | 0.79 | 0.546 | 1.34 | 0.706 | 3.48 | 0.582 |
>M ** | 21 | 0.56 | 0.49 | 2.07 | 3.47 | |||||
Age | ≤50 | 18 | 0.65 | 0.565 | 0.55 | 0.617 | 1.78 | 0.266 | 6.15 | 0.019 |
>50 | 22 | 0.68 | 0.80 | 1.32 | 1.95 |
miRNA | Regulation of miRNA Expression According to Bioinformatic Analysis | Observed Changes | ||
---|---|---|---|---|
MCF-7 | ||||
Estradiol | Testosterone | Progesterone | ||
miR-27a | ER *, AR * | - | down (6 h) | - |
miR-190b | ER *, AR, PR | down (6 h) up (24 h) | - | up (48 h) |
miR-190a | ER *, AR, PR | - | up (48 h) | down (24 h) |
miR-200b | ER *, AR ** | down (6 h) | up (48 h) | - |
miR-21 | ER *, AR *, PR | - | down (6 h) up (48 h) | up (6 h) |
miR-423 | ER, AR, PR | - | up (48 h) | - |
miR-193b | ER, PR, AR | up (48 h) | up (48 h) | - |
miR-324 | ER, PR, AR | up (6 h) | up (48 h) | up (6 h) |
miRNA | Associated Tumor Characteristics |
---|---|
miR-27a | Age of the patients and the level of PR expression. |
miR-190b | ER receptor status. Ki-67 index in ER+ and/or PR+ HER2-expressing, and Ki-67 index in ER− and PR− HER2-amplified tumors. |
miR-190a | Expression level of PR. LN status in ER+ and/or PR+ tumors with low Ki-67. Ki-67 index in triple-negative tumors. |
miR-200b | HER2 status and Ki-67 index. Tumor size in ER+ and/or PR+ tumors with low Ki-67. Level of ER expression in Luminal B tumors not expressing HER2. |
miR-21 | ER receptor status and age of the patients. Expression level of HER2. |
miR-423 | HER2 status and Ki-67 index. LN status in luminal A, luminal B HER2-amplified, and luminal B HER2 1+ tumors. |
miR-193b | LN status in ER+ and/or PR+ tumors (except HER2 1+ cases). Tumor size in ER+ and/or PR+ HER2-non-expressing tumors. Expression level of ER in Luminal B HER2 0 tumors. |
miR-324 | Tumor size in Luminal B HER2-non-amplified tumors. Age of the patients and HER2 status in ER+ and/or PR+ tumors with low Ki-67. |
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Kalinina, T.; Kononchuk, V.; Alekseenok, E.; Abdullin, G.; Sidorov, S.; Ovchinnikov, V.; Gulyaeva, L. Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer. J. Pers. Med. 2022, 12, 4. https://doi.org/10.3390/jpm12010004
Kalinina T, Kononchuk V, Alekseenok E, Abdullin G, Sidorov S, Ovchinnikov V, Gulyaeva L. Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer. Journal of Personalized Medicine. 2022; 12(1):4. https://doi.org/10.3390/jpm12010004
Chicago/Turabian StyleKalinina, Tatiana, Vladislav Kononchuk, Efim Alekseenok, Grigory Abdullin, Sergey Sidorov, Vladimir Ovchinnikov, and Lyudmila Gulyaeva. 2022. "Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer" Journal of Personalized Medicine 12, no. 1: 4. https://doi.org/10.3390/jpm12010004
APA StyleKalinina, T., Kononchuk, V., Alekseenok, E., Abdullin, G., Sidorov, S., Ovchinnikov, V., & Gulyaeva, L. (2022). Associations between the Levels of Estradiol-, Progesterone-, and Testosterone-Sensitive MiRNAs and Main Clinicopathologic Features of Breast Cancer. Journal of Personalized Medicine, 12(1), 4. https://doi.org/10.3390/jpm12010004