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Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor‐negative breast cancer
Author(s) -
Arima Yoshimi,
Hayashi Naoki,
Hayashi Hidemi,
Sasaki Mikako,
Kai Kazuharu,
Sugihara Eiji,
Abe Eriko,
Yoshida Atsushi,
Mikami Shuji,
Nakamura Seigo,
Saya Hideyuki
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26271
Subject(s) - cancer research , breast cancer , sox2 , cd44 , estrogen receptor , cancer stem cell , biology , homeobox protein nanog , cancer , progesterone receptor , cd24 , medicine , cell , transcription factor , embryonic stem cell , biochemistry , genetics , gene , induced pluripotent stem cell
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.