Cytokeratin 5 positive cells represent a steroid receptor negative and therapy resistant subpopulation in luminal breast cancers
- نوع فایل : کتاب
- زبان : انگلیسی
- مؤلف : Peter Kabos James M. Haughian Xinshuo Wang Wendy W. Dye Christina Finlayson Anthony Elias Kathryn B. Horwitz Carol A. Sartorius
- چاپ و سال / کشور: 2010
Description
A majority of breast cancers are estrogen receptor (ER) positive and have a luminal epithelial phenotype. However, these ER? tumors often contain heterogeneous subpopulations of ER- tumor cells. We previously identified a population of cytokeratin 5 (CK5) positive cells within ER? and progesterone receptor positive (PR?) tumors that is both ER-PR- and CD44?, a marker of breast tumor-initiating cells (TICs). These CK5? cells have properties of TICs in luminal tumor xenografts, and we speculated that they are more resistant to chemo- and anti-ER-targeted therapies than their ER? neighbors. To test this, we used ER?PR? T47D and MCF7 breast cancer cells. CK5? cells had lower proliferative indices than CK5- cells, were less sensitive to 5-fluorouracil and docetaxel, and cultures became enriched for CK5? cells after treatments. CK5? cells were less prone to drug-induced apoptosis than CK5- cells. In cells treated with 17b-estradiol (E) plus anti-estrogens tamoxifen or fulvestrant, ER protein levels decreased, and CK5 protein levels increased, compared to controls treated with E alone. In ER? tumors from patients treated with neoadjuvant endocrine therapies ER gene expression decreased, and CK5 gene expression increased in post compared to pre-treatment tumors. The number of CK5? cells in tumors also increased in post- compared to pretreatment tumors. We conclude that an ER-PR-CK5? subpopulation found in many luminal tumors is resistant to standard endocrine and chemotherapies, relative to the majority ER?PR?CK5- cells. Compounds that effectively target these cells are needed to improve outcome in luminal breast cancers.
Breast Cancer Res Treat (2011) 128:45–55 Received: 30 April 2010 / Accepted: 17 July 2010 / Published online: 28 July 2010 Springer Science+Business Media, LLC. 2010
