ERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancer

Petrossian K.Kanaya N.CHIAO LOHsu P.-Y.Nguyen D.Yang L.Yang L.Warden C.Wu X.Pillai R.Bernal L.CHIUN-SHENG HUANGKruper L.Yuan Y.Somlo G.Mortimer J.Chen S.2020-03-232020-03-2320181949-2553https://www.scopus.com/inward/record.uri?eid=2-s2.0-85048365983&doi=10.18632%2foncotarget.25552&partnerID=40&md5=fbebf942e2a0344f0e8d24a03289f658https://scholars.lib.ntu.edu.tw/handle/123456789/477705While 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.enCDK4/6 inhibitorsDEPArraypalbociclibpatient-derived xenografts (PDX)single cell analysis[SDGs]SDG3cyclin 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 expressionERα-mediated cell cycle progression is an important requisite for CDK4/6 inhibitor response in HR+ breast cancerjournal article10.18632/oncotarget.25552299632332-s2.0-85048365983