A model of human triple-negative breast cancer

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Answer

Is there a transgenic model of triple negative breast cancer?

Transgenic Mouse Model of Human Basal Triple Negative Breast Cancer Summary (1024-character limit) NIH scientists created and characterized an excellent mouse model for TNBC that shares important molecular characteristics of human TNBC making it highly useful for preclinical testing of drugs and novel therapies.

What is basal triple negative breast cancer?

Basal triple-negative breast cancer (TNBC) is a common form of human breast cancer for which there are no specific, targeted therapies, unlike hormone-responsive or Her2+ breast cancers. TNBC has a much worse prognosis than hormone receptor + cancer and is disproportionately high in the African-American population.

How is triple negative breast cancer (TNBC) treated?

Triple negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, lacks estrogen receptors, progesterone receptors, and amplification or overexpression of Her-2. As such, these tumors are not responsive to hormonal or anti-Her2 therapies, and are usually treated with combinations of surgery, radiation, and chemotherapy.

What is the prognosis of triple negative breast cancer?

Triple-negative breast cancer (TNBC) is considered an aggressive cancer because it grows quickly, is more likely to have spread at the time it’s found, and is more likely to come back after treatment than other types of breast cancer. The outlook is generally not as good as it is for other types of breast cancer.

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Are there any survivors of triple-negative breast cancer?

However, many of those with TNBC will live long, disease-free lives. The overall 5-year relative survival rate across all stages of the disease is 77%.


What is the life expectancy of someone with triple-negative breast cancer?

In general, about 91% of all women with triple-negative breast cancer are still alive 5 years after diagnosis. If the cancer has spread to the lymph nodes near the breast (regional) the 5 year relative survival rate is about 65%. If the cancer has spread to distant places, the 5 year relative survival rate is 12%.


What is the latest treatment for triple-negative breast cancer?

Pembrolizumab Improves Survival in Advanced Triple-Negative Breast Cancer. Adding the immunotherapy drug pembrolizumab (Keytruda) to chemotherapy can help some patients with advanced triple-negative breast cancer live longer than if they received chemotherapy alone, new results from a clinical trial show.


What is the main cause of triple-negative breast cancer?

What causes triple negative breast cancer? Researchers don’t know what causes TNBC, but they think BRCA1 genetic mutation might play a part. The BRCA1 gene is meant to prevent cancer. When it mutates, however, the gene reverses course and makes your cells more vulnerable to cancer.


Is triple-negative breast cancer the worst kind?

Triple-negative breast cancer accounts for about 10% to 20% of all breast cancer cases. Every cancer diagnosis is unique, but in general, triple-negative breast cancer is a more aggressive type of tumor with a faster growth rate, higher risk of metastasis and recurrence risk.


What is the deadliest form of breast cancer?

Triple-negative breast cancer (TNBC) is considered an aggressive cancer because it grows quickly, is more likely to have spread at the time it’s found, and is more likely to come back after treatment than other types of breast cancer.


Where does triple-negative breast cancer spread first?

Route of first metastasis correlated significantly with survival of TNBC patients with brain metastases being the poorest survival indicator, followed by metastases to liver, pleura, bone, and lung.


Is there hope for triple-negative breast cancer?

According to experts, triple-negative can be a very treatable and potentially curable type of breast cancer, especially with recent research advances. Treatment of triple-negative breast cancer involves both local therapies, such as surgery and radiation, and can also include systemic therapies, like chemotherapy.


Is triple-negative breast cancer hardest to treat?

Triple-negative breast cancer is that which tests negative for three receptors: estrogen, progesterone, and human epidermal growth factor receptor 2 (HER2). It is also the least common form of breast cancer and the hardest to treat.


Does stress cause triple-negative breast cancer?

Social stress connected to triple-negative breast cancer via fat cells. Local chemical signals released by fat cells in the mammary gland appear to provide a crucial link between exposure to unrelenting social stressors early in life and to the subsequent development of breast cancer, according to new research.


How often does triple-negative breast cancer come back?

Targeted therapy allows healthy cells to survive, but chemotherapy can kill normal cells when eliminating the cancer cells. Sixty percent of patients with triple-negative breast cancer will survive more than five years without disease, but four out of ten women will have a rapid recurrence of the disease.


Where does triple negative breast cancer usually spread to?

It has spread to distant organs or to lymph nodes far from the breast. The most common sites of spread are the bone, liver, brain or lung.


Should you have a mastectomy with triple negative breast cancer?

Because triple-negative disease is considered more aggressive than breast cancers that are HER2-positive or hormone-receptor-positive, many doctors believe that it should be removed with mastectomy rather than lumpectomy followed by radiation to reduce the risk of recurrence and improve survival chances.


What is the best chemo for triple negative breast cancer?

Common chemotherapies for triple negative breast cancer may include an anthracycline such as Adriamycin, alkylating agents such as Cytoxan, and a taxane, such as Taxol or Taxotere. Fluorouracil (5FU) may be given as well. Often a combination of drugs, or a “chemo cocktail,” is given to disable and kill cancer cells.


Is Stage 2 triple negative breast cancer curable?

Survival Rate for Patients with Triple-Negative Breast Cancer. Triple-negative breast cancer is considered aggressive, or fast-growing, but it is treatable. Survival depends on factors such as how advanced the cancer was at diagnosis, your overall health, and your response to treatment.


What is triple negative breast cancer?

Triple negative breast cancer (TNBC), accounting for 15-20% of all breast cancers, lacks estrogen receptors, progesterone receptors, and amplification or overexpression of Her-2. As such, these tumors are not responsive to hormonal or anti-Her2 therapies, and are usually treated with combinations of surgery, radiation, and chemotherapy. Although many triple negative tumors respond well to chemotherapy, patients generally have poorer prognosis, higher relapse rates with aggressive tumor growth, and high metastatic potential. More than 300 clinical trials are currently ongoing in TNBC ( www.clinicaltrials.gov) evaluating various single agent and combination approaches with chemotherapy, targeted therapy, immunotherapy, and radiation therapy. Clinically, radiation therapy has been associated with decreased risk of locoregional recurrence and some instances of improved overall survival when compared to patients that did not receive radiation therapy.1, 2


Can triple negative tumors be treated with chemotherapy?

Although many triple negative tumors respond well to chemotherapy, patients generally have poorer prognosis, higher relapse rates with aggressive tumor growth, and high metastatic potential. …


Can HCC70 be used for TNBC?

The HCC70 human TNBC cell line can be used to model this disease preclinically. This cell line grows well following subcutaneous implant in female NSG mice (Figure 1A). To determine which chemotherapy would be suitable for combination approaches we evaluated both paclitaxel and docetaxel. We observed a strong response to docetaxel and a more modest response to paclitaxel (Figure 1B) with minimal effects on body weight loss (Figure 1C). The response to paclitaxel was further verified in an additional study (data not shown).


What is triple negative breast cancer?

Triple-negative breast cancer (TNBC) is a highly diverse group of cancers, and subtyping is necessary to better identify molecular-based therapies. In this study, we analyzed gene expression (GE) profiles from 21 breast cancer data sets and identified 587 TNBC cases. Cluster analysis identified 6 TNBC subtypes displaying unique GE and ontologies, including 2 basal-like (BL1 and BL2), an immunomodulatory (IM), a mesenchymal (M), a mesenchymal stem–like (MSL), and a luminal androgen receptor (LAR) subtype. Further, GE analysis allowed us to identify TNBC cell line models representative of these subtypes. Predicted “driver” signaling pathways were pharmacologically targeted in these cell line models as proof of concept that analysis of distinct GE signatures can inform therapy selection. BL1 and BL2 subtypes had higher expression of cell cycle and DNA damage response genes, and representative cell lines preferentially responded to cisplatin. M and MSL subtypes were enriched in GE for epithelial-mesenchymal transition, and growth factor pathways and cell models responded to NVP-BEZ235 (a PI3K/mTOR inhibitor) and dasatinib (an abl/src inhibitor). The LAR subtype includes patients with decreased relapse-free survival and was characterized by androgen receptor (AR) signaling. LAR cell lines were uniquely sensitive to bicalutamide (an AR antagonist). These data may be useful in biomarker selection, drug discovery, and clinical trial design that will enable alignment of TNBC patients to appropriate targeted therapies.


What are the subtypes of breast cancer?

In addition to cytokeratin expression, breast cancers can be classified by an “intrinsic/UNC” 306-gene set into 5 major subtypes (basal-like, HER2-like, normal breast–like, luminal A, and luminal B) ( 30 ). Since TNBCs are largely considered basal-like, we correlated each of the 386 TNBC tumor profiles to the intrinsic gene set centroids of the 5 molecular subtypes, as previously described ( 30 ). Tumors were assigned to 1 of the molecular subtypes based on the highest correlation coefficient between each TNBC expression profile and the 5 molecular subtype centroids. This analysis resulted in 49% ( n = 188) of our TNBC training set classified as basal-like, 14% ( n = 54) as luminal A, 11% ( n = 42) as normal breast–like, 8% ( n = 31) as luminal B, 5% ( n = 19) as HER2, and 13% ( n = 52) as unclassifiable (Supplemental Figure 13B and Supplemental Table 9). This confirms that most TNBCs classify to the basal-like molecular subtype. Both the unstable tumors and BL1 tumors correlated strongly to the basal-like intrinsic molecular classification (76% and 85%, respectively). However, the BL2, IM, and M subtypes only moderately correlated to the basal-like molecular class (31%, 58%, and 47%, respectively), with a portion of tumors unclassified (22%, 17%, and 18%, respectively) (Supplemental Figure 13B). The M and MSL subtypes displayed the largest portion of tumors classified as normal breast–like (25%, and 46%, respectively). The BL2, M, and MSL subtypes were a mixture of classifications, suggesting the intrinsic classification system may not be suitable for characterizing these TNBC subtypes. The majority of TNBC tumors within the LAR subtype were classified as either luminal A or luminal B (82%), and none were classified as basal-like, further supporting the luminal origin of the LAR subtype (Supplemental Figure 13). While only 49% of the tumors were classified as basal-like according to the intrinsic gene set, IHC staining performed on the Vanderbilt subset of tumors ( n = 25) showed that the majority (88%) of TNBCs stained positive for the basal cytokeratins CK5/6 (Supplemental Table 10). Additionally, 56% of the Vanderbilt tumors stained positive for EGFR, similar to a previous study that found 56% of n = 929 pooled from 34 studies that were positive for EGFR or CK5/6 ( 31 ). There were no statistical differences between CK5/6 and EGFR staining across TNBC subtypes. Thus, the majority of TNBCs display a basal-like phenotype by IHC, while only approximately half correlate to the basal-like intrinsic gene set.


How many TNBC subtypes are there?

k-means and consensus clustering reveal 6 TNBC subtypes. To identify global differences in GE between TNBC subtypes, we performed k-means clustering on the most differentially expressed genes (SD>0.8). Using the silhouette width (s [i]) as a measure of relative closeness of individual samples to their clusters, k-means clustering classified 337 of the 386 TNBC tumors into 6 stable clusters (s [i] > 0) and 49 tumors into 1 unstable cluster (s [i] > 0) (Figure 2 A). Clustering resulted in a distribution of samples in all 7 clusters independent of each data set, n = 14, indicating that confounding factors such as batch effect, RNA amplification, and sample quality did not influence cluster distribution (Supplemental Figure 1). Sample classification robustness was analyzed by consensus clustering, which involves k-means clustering by resampling (1,000 iterations) randomly selected tumor profiles. The consensus matrix is a visual representation of the proportion of times in which 2 samples are clustered together across the resampling iterations (Figure 2 B). Groups of samples that frequently cluster with one another are pictorially represented by darker shades of red. To determine the number of clusters present in the data, we examined the area under the curve of the consensus distribution function (CDF) plot (Figure 2 C). The point at which the area under the curve ceases to show marked increases with additional cluster number (k) indicates the ideal number of clusters (Figure 2 D and ref. 19 ). Therefore, the optimal number of clusters is 7, as defined by the consensus plots consistent with the k-means clustering (6 stable, 1 unstable). Unsupervised dimension reduction by principal component analysis demonstrated fundamental differences in GE between tumor subtypes identified by k-means and consensus clustering (Figure 2 E).


What are the differential sensitivity of TNBC cells?

TNBC cell lines have differential sensitivity to therapeutic agents. There are a variety of targeted therapies undergoing clinical investigation in patients with TNBC including those targeting PARP ( 9 ), AR ( 34 ), Src ( 13 ), and PI3K/mTOR ( 35) signaling. We used the panel of TNBC cell lines to assess differential response to several agents targeting these pathways. For comparison we also analyzed primary human mammary epithelial cells (HMECs) in our cell viability assays. We determined the half-maximal inhibitory concentration (IC 50) values for the following drugs [targets]: veliparib (ABT-888) [PARP1/2]; olaparib (AZD2281) [PARP1/2]; cisplatin [DNA]; bicalutamide [AR]; 17-DMAG [Hsp90]; dasatinib [Src/ Abl]; and NVP-BEZ235 [PI3K and mTOR].


What are TNBC cell models?

Using the bimodal filtering approach on ER, PR, and HER2 GE levels from 2 independent breast cancer cell line data sets (GSE-10890 and ETABM-157), we identified 24 and 25 triple-negative cell lines in the GSE-10890 and ETABM-157 GE data sets, respectively (Supplemental Table 1). Of the cell lines present in both data sets, nearly all had similar predictions of triple-negative status by bimodal filtering. Discrepancies in some cell lines (e.g., HCC1500 and HCC1937) may be the result of differences in culturing methods and/or loss of hormone receptor expression over time in culture. Analysis of these 2 data sets identified 30 nonoverlapping TNBC cell lines.


What are the two basal groups of breast cancer?

Two distinct basal groups (A and B) have been identified by GE profiling of breast cancer cell lines ( 33 ). Basal A cell lines display epithelial characteristics and are associated with BRCA1 gene signatures, while basal B cell lines are more invasive and display mesenchymal and stem/progenitor-like characteristics. Our GE analyses revealed that the majority of basal A cell lines belong to the BL1 and BL2 subtypes, while the majority of basal B cell lines fall into the M and MSL subtypes (Table 3 ). We used hierarchical clustering analysis on all TNBC cell lines using the most differentially expressed genes from the tumors to determine whether GE patterns of the cell lines are similar within TNBC subtypes (Supplemental Figure 17). Three clusters were identified: LAR, containing all 4 LAR lines; basal-like, containing lines in the BL1 and BL2 subtypes; and mesenchymal-like, containing lines in the M and MSL subtypes. This clustering analysis indicates that TNBC cell lines can be classified into 3 main groups: basal-like (BL1 and BL2); mesenchymal-like (M and MSL); and LAR. This classification will be used in subsequent sections.


What is the most common genetic event in breast cancer?

Since activa ting mutations in PIK3CA are the most frequent genetic event in breast cancer ( 40 ), we treated the TNBC cell lines with the dual PI3K/mTOR inhibitor NVP-BEZ235 ( 41 ). TNBC cell lines that have activated PI3K/AKT signaling due to PIK3CA mutations or PTEN deficiency (Table 3) were highly sensitive to NVP-BEZ235 (Figure 6 C). In addition, mesenchymal-like TNBC cell lines were more sensitive to NVP-BEZ235 compared with basal-like cell lines (average IC 50 = 44 nM vs. IC 50 = 201 nM; P = 0.001) (Figure 6, C and D), which may suggest that deregulation of the PI3K pathway is important for this subtype. LAR cell lines were also more sensitive to NVP-BEZ235 compared with basal-like cell lines (average IC 50 = 37 nM vs. 116 nM; P = 0.01) (Figure 6, C and D). This sensitivity can be explained by PIK3CA mutations, frequent in the LAR subtype, with all LAR cell lines containing PIK3CA -activating mutations (HCC2185, MDA-MB-453 CAL-148, MFM-223, and SUM185PE) (Table 3 ). While PIK3CA mutations predicted NVP-BEZ235 sensitivity, PTEN deficiencies (mutation or loss of protein expression) did not correlate with sensitivity.


What is the mouse model for TNBC?

NIH scientists created and characterized an excellent mouse model for TNBC that shares important molecular characteristics of human TNBC making it highly useful for preclinical testing of drugs and novel therapies. This model may provide a valuable means of identifying new drugs and therapies that could be translated to human clinical trials.The NCI seeks parties interested in licensing this mouse model of prostat e and triple-negative breast cancers to study cancer biology and for preclinical testing.


What is TNBC in biology?

The NCI Laboratory of Cancer Biology and Genetics seeks parties interested in collaborative research to further develop this mouse model of triple-negative breast cancer (TNBC) to study cancer biology and for preclinical testing. As a Research Tool, patent protection is not being pursued for this technology; more information to access this strain can be found here: https://www.jax.org/strain/030386 .


Is TNBC a human cancer?

Basal triple-negative breast cancer (TNBC) is a common form of human breast cancer for which there are no specific, targeted therapies, unlike hormone-responsive or Her2+ breast cancers. TNBC has a much worse prognosis than hormone receptor + cancer and is disproportionately high in the African-American population. NIH scientists have created and characterized a transgenic model that is currently an excellent mouse model for TNBC that shares important molecular characteristics of human TNBC making it highly useful for preclinical testing of drugs and novel therapies. This model may provide a valuable means of identifying new drugs and therapies that could be translated to human clinical trials. The mouse model also develops prostate intraepithelial neoplasia and prostate cancer, therefore has also been used for studies of prostate cancer.


What is the mouse model for TNBC?

NIH scientists created and characterized an excellent mouse model for TNBC that shares importantmolecular characteristics of human TNBC making it highly useful for preclinical testing of drugs andnovel therapies. This model may provide a valuable means of identifying new drugs and therapies thatcould be translated to human clinical trials.The NCI seeks parties interested in licensing this mousemodel of prostate and triple-negative breast cancers to study cancer biology and for preclinical testing.


What is TNBC in biology?

The NCI Laboratory of Cancer Biology and Genetics seeks parties interested in collaborative research tofurther develop this mouse model of triple-negative breast cancer (TNBC) to study cancer biology andfor preclinical testing . As a Research Tool, patent protection is not being pursued for this technology;more information to access this strain can be found here: https://www.jax.org/strain/030386.

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