title: Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer.
abstract: Triple-negative breast cancer [TNBC, which is negative for the estrogen receptor (ER), progesterone receptor, and human epidermal growth factor receptor 2] is a high-risk form of the disease without a specific therapy. DNA microarray and immunohistochemical analyses have shown that most TNBCs fall within the basal-like histological subset of breast cancers, which frequently exhibit inactivation of the retinoblastoma tumor suppressor (Rb) and upregulation of the cyclin-dependent kinase inhibitor p16(INK4a)  (p16). However, downregulation of p16 expression has been observed in some basal-like breast cancer cell lines, suggesting that such cells can be divided into two groups according to Rb and p16 status. We now show that cells that are CD44(+)  and CD24(-) , a phenotype associated with stem-like breast cancer cells, are more abundant in ER(-) /p16(-)  breast cancer cell lines than in ER(-) /p16(+)  lines. It was also found that p16 expression was downregulated in mammospheres from an ER-negative breast cancer cell line. Depletion of p16 by RNA interference in ER-negative breast cancer cells increased the percentage of CD44(+) /CD24(-)  cells and increased the expression of mRNA of the ES-like genes Nanog, Oct4, and Sox2 through an Rb-independent pathway. Furthermore, such depletion of p16 reduced chemosensitivity. The loss of p16 expression may thus reduce the response of ER-negative breast cancer cells to chemotherapy by conferring cancer stem cell-like properties. Consistent with this conclusion, immunohistochemical analysis of the clinical samples suggests that low p16 expression in TNBC is associated with resistance to preoperative chemotherapy.
authors: Division of Gene Regulation, Institute for Advanced Medical Research, School of Medicine, Keio University, Tokyo 160-8582, Japan.
authors: Yoshimi
authors: Y
authors: Arima
authors: Naoki
authors: N
authors: Hayashi
authors: Hidemi
authors: H
authors: Hayashi
authors: Mikako
authors: M
authors: Sasaki
authors: Kazuharu
authors: K
authors: Kai
authors: Eiji
authors: E
authors: Sugihara
authors: Eriko
authors: E
authors: Abe
authors: Atsushi
authors: A
authors: Yoshida
authors: Shuji
authors: S
authors: Mikami
authors: Seigo
authors: S
authors: Nakamura
authors: Hideyuki
authors: H
authors: Saya
mesh_terms: D000328:Adult; D000368:Aged; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000473:pathology; D051927:CD24 Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D019941:Cyclin-Dependent Kinase Inhibitor p16; D019008:Drug Resistance, Neoplasm; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D008875:Middle Aged; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins / Q000502:physiology*; D014411:Neoplastic Stem Cells; D050814:Octamer Transcription Factor-3 / Q000235:genetics; D017239:Paclitaxel / Q000494:pharmacology; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000032:analysis; D016160:Retinoblastoma Protein / Q000502:physiology; D055748:SOXB1 Transcription Factors / Q000235:genetics; D051900:Smad3 Protein / Q000378:metabolism
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C497483:CD44 protein, human; C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018398:Homeodomain Proteins; D018960:Hyaluronan Receptors; C486780:NANOG protein, human; D000071317:Nanog Homeobox Protein; D009363:Neoplasm Proteins; D050814:Octamer Transcription Factor-3; C494173:POU5F1 protein, human; D011960:Receptors, Estrogen; D016160:Retinoblastoma Protein; C497790:SMAD3 protein, human; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; D051900:Smad3 Protein; D017239:Paclitaxel