CN118147300A - Application of TMEM132E in diagnosis and treatment of triple negative breast cancer - Google Patents
Application of TMEM132E in diagnosis and treatment of triple negative breast cancer Download PDFInfo
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Abstract
The invention belongs to the technical fields of crude drug medicines and molecular biology, and particularly relates to an application of TMEM132E in diagnosis and treatment of triple negative breast cancer. Specifically, the invention discovers that TMEM132E is abnormally and highly expressed in triple negative breast cancer for the first time, and is closely related to prognosis of triple negative breast cancer patients, further researches prove that inhibiting TMEM132E expression can inhibit proliferation, migration, invasion and epithelial transformation of triple negative breast cancer cells, and simultaneously restore drug sensitivity of triple negative breast cancer to selective estrogen receptor modulators (such as tamoxifen), thereby providing a more favorable means for diagnosis and prognosis evaluation analysis of triple negative breast cancer, and having important significance for research and treatment of triple negative breast cancer. Meanwhile, an experimental foundation is laid for developing the high-efficiency medicine for treating triple negative breast cancer and a new visual field is provided, so that the medicine has good practical application value.
Description
Technical Field
The invention belongs to the technical fields of crude drug medicines and molecular biology, and particularly relates to an application of TMEM132E in diagnosis and treatment of triple negative breast cancer.
Background
The disclosure of this background section is only intended to increase the understanding of the general background of the invention and is not necessarily to be construed as an admission or any form of suggestion that this information forms the prior art already known to those of ordinary skill in the art.
Breast cancer is the most common type of cancer that leads to death in women. Breast cancer can be divided into subtypes based on the level of hormone receptor expressed by tumor cells. Among them, breast cancers lacking Estrogen Receptor (ER), progestin Receptor (PR) and human epidermal growth factor receptor (HER 2) expression are named triple negative breast cancers. Triple negative breast cancers have a higher aggressiveness and a poorer prognosis than other subtypes of breast cancer. Clinically, the existing endocrine therapy is mostly aimed at ER and HER2, so that the endocrine therapy is ineffective for triple negative breast cancer. The only treatment regimen for triple negative breast cancer is chemotherapy, but chemotherapy has significant toxicity. So that although triple negative breast cancer accounts for about 15% of all breast cancer cases, it accounts for 50% of breast cancer related mortality. There is an urgent need for biomarkers that can predict triple negative breast cancer as diagnostic and prognostic indicators or therapeutic targets. Meanwhile, ER alpha is re-expressed in triple negative breast cancer, so that the sensitivity of tumors to endocrine therapy with lower toxicity is increased, and the method is a promising treatment strategy.
Transmembrane protein family 132 (TMEM 132) is a family of genes encoding single transmembrane proteins. This family includes TMEM132A, B, C, D, and E. The TMEM132 family is involved in the development of a variety of cancers. Such as TMEM132A is associated with bladder cancer; TMEM132D is associated with small cell lung, colorectal and ovarian cancer patients and can also be used as a biomarker to predict triple negative breast cancer chemotherapy response. TMEM132E is currently reported to be a pathogenic gene of non-syndrome autosomal recessive inherited deafness, however, the effect of TMEM in tumors is rarely reported.
Disclosure of Invention
Aiming at the defects existing in the prior art, the invention provides the application of TMEM132E in diagnosis and treatment of triple negative breast cancer. In particular, the invention finds that TMEM132E is abnormally high expressed in triple negative breast cancer patients and is associated with a poor prognosis thereof through studies. Meanwhile, the inhibition of TMEM132E expression can inhibit proliferation, migration, invasion and epithelial to mesenchymal transition of triple negative breast cancer cells, and restore sensitivity of triple negative breast cancer to tamoxifen, so that the triple negative breast cancer can be used as a potential biomarker and a treatment target of triple negative breast cancer. Based on the above results, the present invention has been completed.
Specifically, the invention relates to the following technical scheme:
in a first aspect of the invention there is provided the use of a substance for detecting expression levels of TMEM132E in the preparation of any one or more of the following products:
a1 Triple negative breast cancer diagnosis or auxiliary diagnosis products;
a2 Triple negative breast cancer prognosis evaluation or auxiliary prognosis evaluation products.
In a second aspect of the invention, there is provided a system for (assisted) diagnosis or (assisted) prognosis evaluation of triple negative breast cancer, the system comprising:
b1 An analysis unit including: a test substance for determining the expression level of TMEM132E in a test sample of a subject, and;
b2 An evaluation unit including: assessing the disease condition of said subject based on said TMEM132E expression level determined in b 1).
In a third aspect of the present invention, there is provided a method of screening for a triple negative breast cancer drug comprising:
c1 Treating the expressed and/or contained TMEM 132E-containing system with a candidate substance; setting a parallel control without candidate substance treatment;
c2 After step c 1) is completed, detecting the expression level of TMEM132E in the system; if the expression level of TMEM132E is significantly reduced in a system treated with a candidate substance as compared to a parallel control, the candidate substance can be used as a candidate triple negative breast cancer drug.
In a fourth aspect of the invention there is provided the use of a substance which inhibits expression and/or reduces activity of TMEM132E in any one or more of:
d1 Inhibiting proliferation of triple negative breast cancer cells or preparing a product for inhibiting proliferation of triple negative breast cancer cells;
d2 Inhibiting migration and invasion of triple negative breast cancer cells or preparing a product for inhibiting migration and invasion of triple negative breast cancer cells;
d3 Inhibiting triple negative breast cancer growth or preparing a product for inhibiting triple negative breast cancer growth;
d4 Inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue or preparing a product for inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue;
d5 Preparing a product for restoring drug sensitivity of triple negative breast cancer to selective estrogen receptor modulator;
d6 A product for preventing and/or treating triple negative breast cancer is prepared.
The beneficial technical effects of one or more of the technical schemes are as follows:
The technical scheme proves that the TMEM132E is abnormally and highly expressed in the triple-negative breast cancer for the first time, and is closely related to prognosis of the triple-negative breast cancer patient, and further research proves that inhibiting the TMEM132E expression can inhibit proliferation, migration, invasion and epithelial-to-mesenchymal transition of the triple-negative breast cancer cells, and simultaneously restore sensitivity of the triple-negative breast cancer to tamoxifen.
The technical scheme provides a more favorable means for diagnosis and prognosis evaluation analysis of the triple negative breast cancer, and has important significance for research and treatment of the triple negative breast cancer. Meanwhile, an experimental foundation is laid for developing the high-efficiency medicine for treating triple negative breast cancer and a new visual field is provided, so that the medicine has good practical application value.
Drawings
The accompanying drawings, which are included to provide a further understanding of the invention and are incorporated in and constitute a part of this specification, illustrate embodiments of the invention and together with the description serve to explain the invention.
FIG. 1 is a functional genomics finding TMEM132E over-expression in triple negative breast cancer in an embodiment of the invention; differential expression of TMEM132E in breast cancer patients (n=554) and triple negative breast cancer patients (n=100) and normal human (n=76) samples in tcga database. Comparison of expression of tmem132e in 200 cases of different breast cancer receptor subtypes in TCGA database. Representative images of TMEM132E immunohistochemical staining in tissue chips, including non-triple negative breast cancer, triple negative breast cancer and normal tissue. Staining intensity histogram statistics, P-value was calculated by Wilcoxon test. The scale is 50. Mu.m. E. Expression of TMEM132E protein levels in breast cancer cell lines was detected. F. The effect of TMEM132E expression on the disease-free survival of breast cancer patients (n=397) in the TCGA database was assessed using Kaplan-Meier curve. * p <0.05, < p <0.0001.
FIG. 2 is a graph showing that TMEM132E promotes proliferation of triple negative breast cancer cells in an embodiment of the present invention; effect of tmem132e knockout on MDA-MB-231 and MDA-MB-468 cell proliferation (CCK-8 assay, 0 to 72 hours). Absorbance is expressed as the mean ± standard error of three independent experiments. C, D, E and f. Clones formed triple negative breast cancer cell proliferation statistics to detect TMEM132E gene knockout. G and H. TMEM132E was knocked out in MDA-MB-231 and MDA-MB-468 cells, and after 48 hours the cells were stained for EdU. The number of red positive cell proliferation was counted with ImageJ. The scale is 50. Mu.m. I. MDA-MB-231shNC and shTMEM132E cells were subcutaneously injected into armpits of nude mice (3 in each group), euthanized after 24 days, and tumor tissues were taken out for photographing. Tumor weights (in milligrams) were measured for 3 mice per group after 24 days j.. Data are mean ± standard deviation; * P <0.05; * P <0.01; * P <0.001; * P <0.0001, two-factor anova, bonferroni test.
FIG. 3 is a diagram showing TMEM132E promoting migration and invasion of triple negative breast cancer cells in an embodiment of the present invention; scratch test images a and b. Migration capacities of control and TMEM132E knocked out MDA-MB-231 and MDA-MB-468 cells were measured as time points (0, 48 h), magnification 4×. * P <0.01; * P <0.001; * P <0.0001, two-factor anova, dunnett multiple comparison test. Transwell experiments analyze and quantify the migration and invasion capacity of TMEM132E shNC or TMEM132E knockout breast cancer cells (MDA-MB-231 and MDA-MB-468), magnification of 10×. * P <0.05; * P <0.01; * P <0.001; * P <0.0001, two-factor anova, dunnett multiple comparison test. Protein levels of epithelial-mesenchymal transition (EMT) markers (E-cadherein, MMP2, MMP3, TWIST1, SNAIL2 and Vimentin) in shNC/shTMEM E-treated MDA-MB-231 cells (left panel) and MDA-MB-468 cells (right panel). GAPDH was used as an internal reference. F. Correlation plots of TMEM132E and CDH1 in the triple negative breast cancer subtype. The pearson pairwise correlation coefficient shows a negative correlation (r= -0.28) between TMEM132E and CDH1, with a significant correlation (P < 0.0001) between the two. G. Immunohistochemical staining of E-cadherin in xenogeneic tumor specimens expressing or under-expressing TMEM132E was representative. The magnification was 20×.
FIG. 4 shows that depletion of TMEM132E in the examples of the present invention compensates for the deficiency of ERα and inhibits triple negative breast cancer formation. A. The correlation graphs show the effect of TMEM132E and ESR1 in the triple negative breast cancer subtype. The pearson pairwise correlation coefficient shows a negative correlation (r= -0.23) between TMEM132E and ESR1, with a significant correlation (P < 0.0001) between the two. B. RNA level of ESR1 in triple negative breast cancer cells. And determining the expression quantity by RT-qPCR and then carrying out normalization analysis. GAPDH was used as an internal reference. C. Protein levels of ERα and GAPDH in MDA-MB-231 and MDA-MB-468 cells after knockdown treatment. Proliferation of triple negative breast cancer cells treated with shNC and shTMEM E with 2. Mu.M tamoxifen. Proliferation was determined by CCK8 assay, normalized to the day 0 control. Absorbance is expressed as the mean ± standard error of three independent experiments. * P < 0.05; * P < 0.01; * P < 0.001; * P <0.0001, two-sided student t test was used. E and F scratch experiments. The migration capacity of control and TMEM132E knockout triple negative breast cancer cells was measured at the time point of 0, 48 hours. The magnification was 10×. * P <0.0001, two-factor anova, dunnett's multiplex comparison test. Representative images of 72 hours migration and invasion capacity of control and tamoxifen (2 μm) treated shNC and shTMEM E triple negative breast cancer cells were analyzed by G and h.transwell laboratory experiments. I. Quantitative bar graphs of the Transwell chamber migration and invasion assay were measured 72 hours after control and tamoxifen (2 μm) treatment. P < 0.05 is; p < 0.01 is; p < 0.001 is; p <0.0001 is a two-factor anova, dunnett multiple comparison test.
Detailed Description
It should be noted that the following detailed description is illustrative and is intended to provide further explanation of the application. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs.
It is noted that the terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting of exemplary embodiments according to the present application. As used herein, the singular is also intended to include the plural unless the context clearly indicates otherwise, and furthermore, it is to be understood that the terms "comprises" and/or "comprising" when used in this specification are taken to specify the presence of stated features, steps, operations, devices, components, and/or combinations thereof. Experimental methods in the following embodiments, unless specific conditions are noted, are generally in accordance with conventional methods and conditions of molecular biology within the skill of the art, and are fully explained in the literature. See, e.g., sambrook et al, molecular cloning: the techniques and conditions described in the handbook, or as recommended by the manufacturer.
The invention will be further illustrated with reference to specific examples, which are given for the purpose of illustration only and are not to be construed as limiting the invention. If experimental details are not specified in the examples, it is usually the case that the conditions are conventional or recommended by the sales company; materials, reagents and the like used in the examples were commercially available unless otherwise specified.
The skilled artisan will appreciate that the term "expression level" refers to the amount of a gene product present in vivo or in a sample at a particular point in time. The expression level can be measured/quantified/detected, for example, by the protein or mRNA expressed by the gene. Expression levels can be quantified, for example, as follows: the amount of the gene product of interest present in the sample is normalized with the total amount (total protein or mRNA) of the same type of gene product in the same sample or reference sample (e.g., a sample obtained from the same individual at the same time or a portion of the same sample of the same size (weight, volume), or the amount of the gene product of interest/defined sample size (weight, volume, etc.) is determined. The expression level may be measured or detected by any method known in the art, such as methods for direct detection and quantification of a gene product of interest (e.g., mass spectrometry), or methods for indirect detection and measurement of a gene product of interest that typically work by binding the gene product of interest to one or more different molecules or detection devices (e.g., primers, probes, antibodies, protein scaffolds) that are specific for the gene product of interest. It is also known to the skilled person to determine the level of gene copies, which also includes determining the absence or presence of one or more fragments (e.g. by nucleic acid probes or primers, e.g. quantitative PCR, multiplex ligation dependent probe amplification).
The terms "index" and "marker" are used interchangeably herein and refer to a sign or signal of a condition or for monitoring a condition. Such "disorder" refers to a biological state of a cell, tissue or organ, or to a health and/or disease state of an individual. The indicator may be the presence or absence of a molecule including, but not limited to, a peptide, protein, and nucleic acid, or may be a change in the level or pattern of expression of such a molecule in a cell, or tissue, organ, or individual. The indicator may be the occurrence, development or presence of a disease in an individual or a sign of further progression of such a disease. The indicator may also be a sign of the risk of developing a disease in the individual.
In particular, in one exemplary embodiment of the present invention, there is provided the use of a substance for detecting the expression level of TMEM132E for the preparation of any one or more of the following products:
a1 Triple negative breast cancer diagnosis or auxiliary diagnosis products;
a2 Triple negative breast cancer prognosis evaluation or auxiliary prognosis evaluation products.
According to the invention, compared with normal breast tissues, TMEM132E is highly expressed in breast cancer tissues, especially triple negative breast cancer tissues. Meanwhile, the disease-free survival time of the triple negative breast cancer patients with higher TMEM132E expression level is greatly shortened. Therefore, TMEM132E can be used as a novel triple negative breast cancer biomarker, and provides a basis for diagnosis and prognosis evaluation of triple negative breast cancer.
In the application a 2), the prognosis evaluation of the triple negative breast cancer at least comprises the evaluation of the disease-free survival period of the triple negative breast cancer patient.
In yet another embodiment of the present invention, reagents for detecting TMEM132E include, but are not limited to, reagents for detecting the transcriptional level of TMEM132E in a sample to be tested based on RT-PCR, real-time quantitative PCR, in situ hybridization, gene chip, and gene sequencing; or a reagent for detecting the expression level of TMEM132E in the sample to be detected based on ELISA, colloidal gold test strips, protein chips and other immune detection methods.
The sample to be tested can be a breast related sample of a subject, such as breast tissue, breast cells, blood, lymph fluid and the like.
In still another embodiment of the present invention, the product may be a detection kit, a detection device or an apparatus, which is not particularly limited herein.
In yet another embodiment of the invention, a system for (assisted) diagnosis or (assisted) prognosis evaluation of triple negative breast cancer is provided, the system comprising:
b1 An analysis unit including: a test substance for determining the expression level of TMEM132E in a test sample of a subject, and;
b2 An evaluation unit including: assessing the disease condition of said subject based on said TMEM132E expression level determined in b 1).
In yet another embodiment of the present invention, the prognostic evaluation or auxiliary prognostic evaluation includes evaluating disease-free survival of the subject.
The sample to be tested can be a breast related sample of a subject, such as breast tissue, breast cells, blood, lymph fluid and the like.
In yet another embodiment of the present invention, there is provided the use of TMEM132E as described above as a target in the treatment of triple negative breast cancer and/or screening of triple negative breast cancer drugs.
In yet another embodiment of the present invention, the triple negative breast cancer drug is a drug for preventing and/or treating triple negative breast cancer.
In yet another embodiment of the present invention, there is provided a method of screening for a triple negative breast cancer drug comprising:
c1 Treating the expressed and/or contained TMEM 132E-containing system with a candidate substance; setting a parallel control without candidate substance treatment;
c2 After step c 1) is completed, detecting the expression level of TMEM132E in the system; if the expression level of TMEM132E is significantly reduced in a system treated with a candidate substance as compared to a parallel control, the candidate substance can be used as a candidate triple negative breast cancer drug.
In yet another embodiment of the present invention, the system may be a cellular system, a subcellular system, a solution system, a tissue system, an organ system, or an animal system.
In yet another embodiment of the present invention, there is provided the use of a substance that inhibits TMEM132E expression and/or reduces its activity in any one or more of the following:
d1 Inhibiting proliferation of triple negative breast cancer cells or preparing a product for inhibiting proliferation of triple negative breast cancer cells;
d2 Inhibiting migration and invasion of triple negative breast cancer cells or preparing a product for inhibiting migration and invasion of triple negative breast cancer cells;
d3 Inhibiting triple negative breast cancer growth or preparing a product for inhibiting triple negative breast cancer growth;
d4 Inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue or preparing a product for inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue;
d5 Preparing a product for restoring drug sensitivity of triple negative breast cancer to selective estrogen receptor modulator;
d6 A product for preventing and/or treating triple negative breast cancer is prepared.
Among these, substances that inhibit TMEM132E expression and/or reduce its activity include, but are not limited to, RNA interfering molecules or antisense oligonucleotides, small molecule inhibitors, siRNA, shRNA directed against TMEM132E, substances that effect lentiviral infection or gene knockout, and specific antibodies, such as anti-TMEM 132E antibodies, directed against TMEM132E itself or molecules upstream and downstream thereof.
The product can be a drug or a test reagent which can be used for basic research so as to research the related mechanism of occurrence and development of triple negative breast cancer.
The selective estrogen receptor modulator may be tamoxifen.
When the product is a medicament, the medicament further comprises at least one pharmaceutically inactive ingredient.
The pharmaceutically inactive ingredients may be carriers, excipients, diluents and the like which are generally used in pharmacy. Further, the composition can be formulated into various dosage forms such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, sprays, etc., for oral administration, external use, suppositories, and sterile injectable solutions according to a usual method.
In yet another embodiment of the invention, the medicament of the invention may be administered to the body in a known manner. For example, by intravenous systemic delivery or local injection into the tissue of interest. Alternatively via intravenous, transdermal, intranasal, mucosal or other delivery methods. Such administration may be via single or multiple doses. It will be appreciated by those skilled in the art that the actual dosage to be administered in the present invention may vary greatly depending on a variety of factors, such as the target cell, the type of organism or tissue thereof, the general condition of the subject to be treated, the route of administration, the mode of administration, and the like.
The invention is further illustrated by the following examples, which are not to be construed as limiting the invention. It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. In an example, transcripts of TMEM132E gene are: NM_001304438.2, shRNA designed for TMEM132E (shTMEM 132E) has the sequence: 5'-TGAAGTCACTGACTAGGTC-3' (SEQ ID NO. 1).
Examples
TMEM132E is remarkably high-expressed in triple-negative breast cancer, and the disease-free survival time of patients is shortened
We analyzed the breast cancer tissue chip dataset downloaded from the cancer genomic map (TCGA), and found that TMEM132E was highly expressed in breast cancer tissues, especially triple negative breast cancer tissues, compared to normal breast tissues (fig. 1a,1 b). Analysis in the tissue chip further using immunohistochemical method confirmed the high expression of TMEM132E in triple negative breast cancer tissue (fig. 1C, D). At the same time, the Western immunoblotting method is used for detection, and TMEM132E is found to express significantly higher than normal human mammary epithelial cell lines MCF10A, non-triple negative breast cancer cell lines T-47D and MCF7 in triple negative breast cancer cell lines MDA-MB-231, MDA-MB-436 and MDA-MB-468 (figure 1E). It was also found that the disease-free survival of patients with triple negative breast cancer with higher levels of TMEM132E expression was greatly shortened compared to patients with triple negative breast cancer with lower levels of TMEM132E expression (fig. 1F). The above results indicate that TMEM132E can be a potential biomarker for monitoring breast cancer progression and predicting clinical outcome.
2. Knockout of TMEM132E inhibits triple negative breast cancer cell proliferation and tumor growth
We knockdown TMEM132E expression in the triple negative breast cancer cell strain by lentivirus shRNA, and found that TMEM132E knockdown significantly reduced proliferation of the triple negative breast cancer cells by CCK-8 detection (FIGS. 2A, B); clone formation experiments showed that TMEM132E knockdown reduced the clonogenic capacity of triple negative breast cancer cells (fig. 2C, D, E, F); the EdU incorporation experiments showed a significant decrease in the proportion of TMEM132E knockdown group EdU positive cells, indicating a decrease in cell proliferation (fig. 2G, H). In BALB/c nude mice tumor-bearing experiments, TMEM132E knockdown group had reduced tumor volume and decreased mass compared to control group (fig. 2i,2 j). The above results demonstrate that TMEM132E knockout inhibits triple negative breast cancer cell proliferation and tumor growth.
TMEM132E knockdown inhibits migration, invasion and epithelial to mesenchymal transition of triple negative breast cancer cells
The mobility of TMEM132E knockout cells (MDA-MB-231 and MDA-MB-468) was found to be significantly reduced in wound healing experiments (fig. 3A, B). Transwell experiments with or without Matrigel were evaluated for tumor cell migration and invasion capacity. The ability of TMEM132E knockdown to migrate and invade cells was found to be significantly reduced (fig. 3C, D). MMP2 and MMP3 levels were significantly reduced in the TMEM132E knockdown triple negative breast cancer cell line compared to the control group (FIG. 3E). The results indicate that knocking down TMEM132E will inhibit migration and invasion of triple negative breast cancer cells by down regulating the expression of MMP2 and MMP 3.
To investigate the involvement of TMEM132E in epithelial to mesenchymal transition we analyzed the expression of epithelial to mesenchymal transition related markers. Upon knockout of TMEM132E, the interstitial markers Snail1, snail2, TWIST1, MMP2, MMP3 and Vimentin were reduced, while the epithelial marker E-cadherein expression was up-regulated (fig. 3E). Analysis of gene expression in the data sets of breast invasive carcinoma in TCGA and PANCANCER databases found that mRNA levels of TMEM132E and CDH1 were inversely correlated (r= -0.28, p <0.0001; fig. 3F), consistent with the up-regulation of E-cadherein expression observed in TMEM132E knockdown triple negative breast cancer cells. Immunohistochemical staining of tumor tissue of the nude mouse xenograft model also observed up-regulation of E-cadherin expression in shTMEM E group (FIG. 3G), indicating that TMEM132E knockout inhibited the epithelial-to-mesenchymal transition process of triple negative breast cancer cells.
4. Knocking down TMEM132E induces re-expression of era to restore sensitivity of triple negative breast cancer to tamoxifen
Era is encoded by the ESR1 gene, whereas ESR1 gene is not normally expressed in triple negative breast cancer cells due to epigenetic mechanisms. To investigate whether TMEM132E affects expression of erα in triple negative breast cancer, we analyzed the gene expression data of the breast invasive carcinoma (TCGA, panCancer) dataset, which showed that TMEM132E mRNA levels were inversely correlated with ESR1 mRNA levels (r= -0.23, p <0.0001; fig. 4A). In triple negative breast cancer cells, ESR1 mRNA levels were elevated when TMEM132E knocked out (fig. 4B), and era expression levels were also significantly increased (fig. 4C). These findings indicate that TMEM132E knockdown may induce re-expression of erα in triple negative breast cancer cells.
We further investigated whether TMEM132E inhibition restored the sensitivity of triple negative breast cancer cells to ER positive breast cancer therapies (e.g., selective ER receptor modulator tamoxifen). CCK-8 experiments showed that tamoxifen and TMEM132E knockout combined treatment significantly reduced proliferation of MDA-MB-231 and MDA-MB-468 cells compared to the single knockout of TMEM132E (FIG. 4D). The results of wound healing, transwell migration and invasion experiments showed that tamoxifen in combination with TMEM132E gene knockout significantly reduced the migration and invasion capacity of triple negative breast cancer cells (fig. 4E-I). These results indicate that TMEM132E gene knockout in combination with tamoxifen treatment can attenuate proliferation, migration and invasive capacity of triple negative breast cancer cells or can be an efficient method of treating triple negative breast cancer.
Finally, it should be noted that: the foregoing description is only a preferred embodiment of the present invention, and the present invention is not limited thereto, but it is to be understood that modifications and equivalents of some of the technical features described in the foregoing embodiments may be made by those skilled in the art, although the present invention has been described in detail with reference to the foregoing embodiments. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention should be included in the protection scope of the present invention.
Claims (10)
1. Use of a substance that detects TMEM132E expression levels in the preparation of any one or more of the following products:
a1 Triple negative breast cancer diagnosis or auxiliary diagnosis products;
a2 Triple negative breast cancer prognosis evaluation or auxiliary prognosis evaluation products.
2. The use of claim 1, wherein in a 2) the prognosis evaluation of triple negative breast cancer comprises at least an evaluation of the disease-free survival of a triple negative breast cancer patient.
3. The use according to claim 1, wherein the reagents for detecting TMEM132E comprise reagents for detecting the transcriptional level of TMEM132E in a sample to be tested based on RT-PCR, real-time quantitative PCR, in situ hybridization, gene chip and gene sequencing; or a reagent for detecting the expression level of TMEM132E in the sample to be detected based on ELISA, colloidal gold test strips and protein chips;
The sample to be detected is a sample related to the breast of a subject, and comprises breast tissue, breast cells, blood and lymph fluid;
the product is a detection kit, a detection device or equipment.
4. A system for (assisted) diagnosis or (assisted) prognosis evaluation of triple negative breast cancer, characterized in that the system comprises:
b1 An analysis unit including: a test substance for determining the expression level of TMEM132E in a test sample of a subject, and;
b2 An evaluation unit including: assessing the disease condition of said subject based on said TMEM132E expression level determined in b 1).
5. The system of claim 4, wherein the prognostic or auxiliary prognostic assessment comprises assessing disease-free survival of the subject.
The application of TMEM132E as a target in the treatment and/or screening of triple negative breast cancer medicaments.
7. Use of a substance that inhibits TMEM132E expression and/or reduces its activity in any one or more of the following:
d1 Inhibiting proliferation of triple negative breast cancer cells or preparing a product for inhibiting proliferation of triple negative breast cancer cells;
d2 Inhibiting migration and invasion of triple negative breast cancer cells or preparing a product for inhibiting migration and invasion of triple negative breast cancer cells;
d3 Inhibiting triple negative breast cancer growth or preparing a product for inhibiting triple negative breast cancer growth;
d4 Inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue or preparing a product for inhibiting transformation of triple negative breast cancer cell epithelium into mesenchymal tissue;
d5 Preparing a product for restoring drug sensitivity of triple negative breast cancer to selective estrogen receptor modulator;
d6 A product for preventing and/or treating triple negative breast cancer is prepared.
8. The use according to claim 7, wherein the substances that inhibit TMEM132E expression and/or reduce TMEM132E activity comprise RNA interfering molecules or antisense oligonucleotides, small molecule inhibitors, siRNA, shRNA directed against TMEM132E, substances that effect lentiviral infection or gene knockout, and specific antibodies directed against TMEM132E itself or upstream and downstream molecules thereof, including anti-TMEM 132E antibodies.
9. The use according to claim 7, wherein the product is a pharmaceutical or test agent.
10. The use according to claim 7, wherein the selective estrogen receptor modulator is tamoxifen.
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