Journal
BIOCHEMICAL PHARMACOLOGY
Volume 190, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bcp.2021.114635
Keywords
HER2-positive breast cancer; Trastuzumab-resistance; SK-BR-3 tumorsphere; Quiescence; Cytoplasmic estrogen receptor alpha; Tamoxifen
Categories
Funding
- National RAMP
- D Program for Cancer Control, Ministry of Health AMP
- Welfare, Republic of Korea [1320060]
- Na-tional Research Foundation of Korea (NRF) - Ministry of Education [NRF2015R1D1A1A01059738, 2018R1D1A1B07049009]
- Korea Health Promotion Institute [1320060] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
- National Research Foundation of Korea [2018R1D1A1B07049009] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
Ask authors/readers for more resources
This study investigated the mechanism underlying trastuzumab resistance in a quiescent cell population and found that the crosstalk between cytoplasmic ERa and the HER2/EGFR signaling pathway is a novel therapeutic target for HER2-positive breast cancer. Combination therapy of tamoxifen and trastuzumab may overcome trastuzumab resistance in HER2-positive breast cancer patients, providing a new treatment strategy.
Since trastuzumab-resistance remains a major obstacle to the successful treatment of HER2-positive breast cancer, a detailed understanding of the mechanisms responsible is required to direct future pharmacotherapeutic strategies. Recently, several studies have indicated that the quiescent natures of cancer stem cells contribute to treatment resistance and tumor recurrence. Thus, in this study, we investigated the mechanism underlying trastuzumab resistance in a quiescent cell population using tumorsphere cultures and explored better therapeutic strategies to overcome trastuzumab resistance in HER2-positive breast cancer patients. We observed that most cells in SK-BR-3 tumorspheres were quiescent, showing the accumulation of cells at the G0/G1 phase as compared to cells in monolayer culture. Furthermore, SK-BR-3 tumorspheres exhibited enhanced EGFR/HER2 signaling, which was incompletely inhibited by trastuzumab, and subsequently led to trastuzumab-resistance. Interestingly, cytoplasmic estrogen receptor alpha (ER alpha) expression was markedly elevated in tumorspheres and was associated with enhanced EGFR/HER2 signaling. Accordingly, inhibition of ERa with tamoxifen selectively targeted tumorspheres rather than cells in monolayer culture and overcame trastuzumab resistance in tumorspheres. Taken together, our findings indicate that crosstalk between cytoplasmic ERa and the HER2/EGFR signaling pathway can be considered a novel therapeutic target for quiescent cell populations within HER2-positive breast cancer and that simultaneous inhibition of ER and the EGFR/HER2 pathway may prevent trastuzumab resistance. We hope that these results provide a basis for the use of combinations of tamoxifen and trastuzumab in HER2-positive breast cancer patients.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available