ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer
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Karineh Petrossian1, Noriko Kanaya1, Chiao Lo2, Pei-Yin Hsu1, Duc Nguyen1, Lixin Yang3, Lu Yang4, Charles Warden4, Xiwei Wu4, Raju Pillai3, Lauren Bernal1, Chiun-Sheng Huang2, Laura Kruper5, Yuan Yuan6, George Somlo6, Joanne Mortimer6 and Shiuan Chen1
1Department of Cancer Biology, Beckman Research Institute of the City of Hope, Duarte, CA, United States
2Department of Breast Health, National Taiwan University Hospital, Taipei City, Taiwan
3Molecular Pathology Core, Beckman Research Institute of the City of Hope, Duarte, CA, United States
4Integrative Genomics Core, Beckman Research Institute of the City of Hope, Duarte, CA, United States
5Department of Surgery, City of Hope Medical Center, Duarte, CA, United States
6Department of Medical Oncology and Therapeutics Research, City of Hope Medical Center, Duarte, CA, United States
Shiuan Chen, email: [email protected]
Keywords: CDK4/6 inhibitors; palbociclib; patient-derived xenografts (PDX); single cell analysis; DEPArray
Received: January 04, 2018 Accepted: May 19, 2018 Published: June 12, 2018
While ER has multiple biological effects, ER-cyclin D1-CDK4/6-RB is a critical pathway for the action of estrogen on the cell cycle, especially for breast cancers that rely on estrogen for growth. The latest and most efficient CDK4/6 inhibitors target the phosphorylation of retinoblastoma (RB) tumor suppressor gene; thus, altering levels of many cell cycle molecules. Estrogen receptor (ER)+/HER2- breast cancers have shown great progression free survival when CDK4/6 inhibitors are combined with endocrine therapies. Here we report the mechanism of antiestrogen (fulvestrant) combination with CDK4/6 inhibitors is due to synergism in the suppression of ER-mediated cell cycle progression. Furthermore, we performed single cell analysis of cells from an estrogen dependent/hormone receptor-positive patient derived xenograft (PDX) tumor model treated with palbociclib. These single cells expressed various levels of ER and RB which are involved in cell cycle regulation; and the response to palbociclib treatment relies not only on the ER-cyclin D1-CDK4/6-RB pathway but it is also dependent on elevated levels of ER and/or RB. Our preclinical studies show that palbociclib response is dependent on cells with ER, which is directly involved in cell cycle progression in hormone receptor positive (HR+) breast cancer.
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