scholarly journals HER2/neu Oncogene and Sensitivity to the DNA-Interactive Drug Doxorubicin

2020 ◽  
Vol 4 (1) ◽  
Author(s):  
Anne Mullin ◽  
Bertrand Jean-Claude

Breast tumor cells overexpressing the proto-oncogene HER2/neu are known to be less responsive to certain DNA-binding chemotherapeutic agents. The current study specifically investigates the correlation between chemosensitivity to the DNA-binding drug doxorubicin and cellular HER2/neu protein levels in a panel of eight breast cancer cell lines (HS-578, BT-474, MDA-MB-453, MDA-MB-231, MDA-MB-175, MCF-7, ZR-75-1 and T47D). The IC50 (the drug concentration required to inhibit cell growth by 50%) values for the cell lines were determined by the sulforhodamine B assay. IC50 values were correlated with HER2/neu protein levels determined by Western blotting. An almost linear relationship between IC50 and HER2/neu protein level for seven cell lines (p = 0.02, r2 = 0.680) was found, with protein levels increasing as resistance increased. The findings suggest that overexpression of HER2/neu correlates with increased resistance to doxorubicin in seven of eight breast cancer cell lines studied. The observation that, in one cell line (MDA-MB-175), doxorubicin IC50 did not correlate with HER2/neu levels, suggests that in these cells, an as-of-yet unidentified factor contributes to resistance. If the observed correlation, which was present in seven of eight cell lines, is confirmed in a larger sample size, increased HER2/neu levels may be implemented as a predictor of breast tumor sensitivity to doxorubicin.

Pathogens ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 641
Author(s):  
Kaitlin M. Branch ◽  
Erica C. Garcia ◽  
Yin Maggie Chen ◽  
Matthew McGregor ◽  
Mikayla Min ◽  
...  

Breast cancer is the leading cause of cancer deaths among women worldwide. There are many known risk factors for breast cancer, but the role of infectious disease remains unclear. Human cytomegalovirus (HCMV) is a widespread herpesvirus that usually causes little disease. Because HCMV has been detected in breast tumor biopsy samples and is frequently transmitted via human breast milk, we investigated HCMV replication in breast tumor cells. Four human breast cancer cell lines with different expression profiles for the key diagnostic markers of the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2), were infected with a bacterial artificial chromosome-derived HCMV clinical strain TB40/E tagged with green fluorescent protein (GFP). Fluorescence microscopy confirmed that all four breast cancer cell lines supported virus entry. RNA was isolated from infected cells and the expression of immediate early (UL123), early (UL54), and late (UL111A) genes was confirmed using PCR. Viral proteins were detected by immunoblotting, and viral progeny were produced during the infection of breast tumor cells, as evidenced by subsequent infection of fibroblasts with culture supernatants. These results demonstrate that breast tumor cells support productive HCMV infection and could indicate that HCMV replication may play a role in breast cancer progression.


2002 ◽  
Vol 96 (Sup 2) ◽  
pp. A75
Author(s):  
Michiko Yamaguchi ◽  
Toshiya Tsujita ◽  
Hiroshi Miyoshi ◽  
Sachiko Todoroki ◽  
Koji Sumikawa

2014 ◽  
Vol 145 (3) ◽  
pp. 581-591 ◽  
Author(s):  
Azadeh Motevalli ◽  
Hemad Yasaei ◽  
Sara Anjomani Virmouni ◽  
Predrag Slijepcevic ◽  
Terry Roberts

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13070-13070 ◽  
Author(s):  
W. Miao ◽  
M. Loignon ◽  
L. Hu ◽  
M. Basik ◽  
G. Batist

13070 Background: Nrf2 is a master transcription factor regulating multiple phase II carcinogen-detoxifying enzymes. Modulating Nrf2 is a current chemoprevention strategy under investigation. Nrf2 levels are regulated by the Keap1, which functions as a substrate adaptor protein targeting Nrf2 to the Cullin-3 (Cul3)-dependent ubiquitin E3 ligase complex. Methods: We used RT-PCR and Western blot to measure the mRNA and protein levels of Nrf2, Keap1 and Cul3 in human breast cancer cell lines. SiRNA and retrovectors were used to construct stable Cul3 silenced breast cancer cell lines. Agilent DNA microarray analysis was used to study the Cul3-slienced cells. Results: We discovered that Nrf2 protein levels in both nucleus and cytoplasm are significantly decreased in all breast cancer cell lines examined compared to normal human mammary epithelial cells (HMEC). This was confirmed with IHC analysis in 8 out of 10 breast cancer specimens containing normal mammary tissues for comparison. Since RT-PCR showed no change in Nrf2 mRNA levels in the breast cancer cell lines, we examined the degradation pathway of Nrf2, and we found that Cul3 is significantly overexpressed in all three breast cancer cell lines studied compared to HMEC. Silencing Cul3 using siRNA results in restoration of Nrf2 protein level, along with multiple carcinogen-detoxifying enzymes, such as GCS. The Cul3 silenced cells showed remarkable growth retardation compared to the wild type MCF-7 cell line both in vitro and in vivo in a mouse mammary fat pad cancer xenograft model. Microarray analyses of Cul3 siRNA-slinced cells demonstrated upregulation of several detoxifying genes, altered cell cycle markers and several upregulated tumor suppressor genes. Conclusions: Nrf2 is significantly downregulated in breast cancer cells, which is related to the overexpression of Cul3, and may represent sensitivity of these cells to carcinogenic transformation. Knocking down Cul3 constitutively upregulates the Nrf2 as well as multiple carcinogen-detoxifying genes. Moreover, it significantly suppressess the proliferation of cancer cells in vitro and growth of xenograft tumors in vivo. These data suggest that Cul-3 is a potential new target for breast cancer chemoprevention and treatment. No significant financial relationships to disclose.


2018 ◽  
Vol 8 (3) ◽  
pp. 159 ◽  
Author(s):  
Meghan Fragis ◽  
Abdulmonem I. Murayyan ◽  
Suresh Neethirajan

Background: Breast cancer is the most commonly diagnosed cancer and the second leading cause of cancer deaths among Canadian women. Cancer management through changes in lifestyle, such as increased intake of foods rich in dietary flavonoids, have been shown to decrease the risk associated with breast, liver, colorectal, and upper-digestive cancers in epidemiologic studies. Onions are high in flavonoid content and one of the most common vegetables. Additionally, onions are used in most Canadian cuisines.Methods: We investigated the effect of five prominent Ontario grown onion (Stanley, Ruby Ring, LaSalle, Fortress, and Safrane) extracts on two subtypes of breast cancer cell lines: a triple negative breast cancer line MDA-MB-231 and an ER+ breast cancer line MCF-7.Results: These onion extracts elicited strong anti-proliferative, anti-migratory, and cytotoxic activities on both the cancer cell lines. Flavonoids present in these onion extracts induced apoptosis, cell cycle arrest in the G2/M phase, and a reduction in mitochondrial membrane potential at dose-dependent concentrations. Onion extracts were more effective against MDA-MB-231 compared to the MCF-7 cell line. Conclusion: In this study, we investigated the extracts synthesized from Ontario-grown onion varieties in inducing anti-migratory, cytostatic, and cytotoxic activities in two sub-types of human breast cancer cell lines. Anti-tumor activity of these extracts depends upon the varietal and can be formulated into nutraceuticals and functional foods for the wellbeing of cancer patients. Overall, the results suggest that onion extracts are a good source of flavonoids with anti-cancerous properties.Keywords: onion extracts; flavonoids; anti-proliferative; breast cancer; cytotoxic activity


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