ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer
Journal
Oncotarget
Journal Volume
9
Journal Issue
45
Pages
27736-27751
Date Issued
2018
Author(s)
Petrossian K.
Kanaya N.
Hsu P.-Y.
Nguyen D.
Yang L.
Yang L.
Warden C.
Wu X.
Pillai R.
Bernal L.
Kruper L.
Yuan Y.
Somlo G.
Mortimer J.
Chen S.
Abstract
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 ERmediated 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. ? Petrossian et al.
Subjects
CDK4/6 inhibitors
DEPArray
palbociclib
patient-derived xenografts (PDX)
single cell analysis
SDGs
Other Subjects
cyclin D1; cyclin dependent kinase 4; cyclin dependent kinase 6; cyclin dependent kinase inhibitor; epidermal growth factor receptor 2; estrogen receptor alpha; fulvestrant; palbociclib; retinoblastoma protein; animal cell; animal experiment; animal model; antineoplastic activity; antiproliferative activity; Article; cancer combination chemotherapy; cancer inhibition; cell cycle progression; controlled study; drug mechanism; drug potentiation; estrogen receptor positive breast cancer; female; G2 phase cell cycle checkpoint; human; human tissue; mouse; nonhuman; progression free survival; protein expression
Publisher
Impact Journals LLC
Type
journal article