Cancer stem cell phenotypes in ER+ breast cancer models are promoted by PELP1/AIB1 complexes

Thu H. Truong, Hsiangyu Hu, Nuri A Temiz, Kyla M. Hagen, Brian J. Girard, Nicholas J. Brady, Kaylee Schwertfeger, Carol A Lange, Julie H Ostrander

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Proline, glutamic acid, leucine-rich protein 1 (PELP1) is overexpressed in approximately 80% of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, interacting partners unique to cytoplasmic PELP1 and the mechanisms by which these interactions promote oncogenic PELP1 signaling were sought. AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) was identified as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor-positive (ER+) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1 at Thr24, enhanced ALDH+ tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, limited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line. Furthermore, in vivo syngeneic tumor studies revealed that PELP1 knockdown resulted in increased survival of tumor-bearing mice as compared with mice injected with control cells. Implications: These data demonstrate that cytoplasmic PELP1/ AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression. Mol Cancer Res; 16(4); 707-19

Original languageEnglish (US)
Pages (from-to)707-719
Number of pages13
JournalMolecular Cancer Research
Volume16
Issue number4
DOIs
StatePublished - Apr 1 2018

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Neoplastic Stem Cells
Breast Neoplasms
Phenotype
human PELP1 protein
Neoplasms
Cytoplasm
Tumor Cell Line
Estrogen Receptors
Small Interfering RNA
Genes
Estrogens
Breast
Stem Cells
Down-Regulation

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

Cite this

Cancer stem cell phenotypes in ER+ breast cancer models are promoted by PELP1/AIB1 complexes. / Truong, Thu H.; Hu, Hsiangyu; Temiz, Nuri A; Hagen, Kyla M.; Girard, Brian J.; Brady, Nicholas J.; Schwertfeger, Kaylee; Lange, Carol A; Ostrander, Julie H.

In: Molecular Cancer Research, Vol. 16, No. 4, 01.04.2018, p. 707-719.

Research output: Contribution to journalArticle

Truong, Thu H. ; Hu, Hsiangyu ; Temiz, Nuri A ; Hagen, Kyla M. ; Girard, Brian J. ; Brady, Nicholas J. ; Schwertfeger, Kaylee ; Lange, Carol A ; Ostrander, Julie H. / Cancer stem cell phenotypes in ER+ breast cancer models are promoted by PELP1/AIB1 complexes. In: Molecular Cancer Research. 2018 ; Vol. 16, No. 4. pp. 707-719.
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abstract = "Proline, glutamic acid, leucine-rich protein 1 (PELP1) is overexpressed in approximately 80{\%} of invasive breast tumors. PELP1 dynamically shuttles between the nucleus and cytoplasm, but is primarily nuclear in normal breast tissue. However, altered localization of PELP1 to the cytoplasm is an oncogenic event that promotes breast cancer initiation and progression. Herein, interacting partners unique to cytoplasmic PELP1 and the mechanisms by which these interactions promote oncogenic PELP1 signaling were sought. AIB1 (amplified in breast cancer 1; also known as SRC-3 or NCOA3) was identified as a novel binding partner of cytoplasmic PELP1 in both estrogen receptor-positive (ER+) and ER-negative cell lines. Cytoplasmic PELP1 expression elevated basal phosphorylation levels (i.e., activation) of AIB1 at Thr24, enhanced ALDH+ tumorsphere formation, and upregulated specific target genes independently of hormone stimulation. Direct manipulation of AIB1 levels using shRNA abrogated cytoplasmic PELP1-induced tumorsphere formation and downregulated cytoplasmic PELP1-specific target genes. SI-2, an AIB1 inhibitor, limited the PELP1/AIB1 interaction and decreased cytoplasmic PELP1-induced tumorsphere formation. Similar results were observed in a murine-derived MMTV-AIB1 tumor cell line. Furthermore, in vivo syngeneic tumor studies revealed that PELP1 knockdown resulted in increased survival of tumor-bearing mice as compared with mice injected with control cells. Implications: These data demonstrate that cytoplasmic PELP1/ AIB1-containing complexes function to promote advanced cancer phenotypes, including outgrowth of stem-like cells, associated with estrogen-independent breast cancer progression. Mol Cancer Res; 16(4); 707-19",
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