Loss of p16 expression is associated with the stem cell characteristics of surface markers and therapeutic resistance in estrogen receptor-negative breast cancer

Yoshimi Arima, Naoki Hayashi, Hidemi Hayashi, Mikako Sasaki, Kazuharu Kai, Eiji Sugihara, Eriko Abe, Atsushi Yoshida, Shuji Mikami, Seigo Nakamura, Hideyuki Saya

Research output: Contribution to journalArticle

50 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)2568-2579
Number of pages12
JournalInternational Journal of Cancer
Volume130
Issue number11
DOIs
Publication statusPublished - 01-06-2012

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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