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Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer
Linköping University, Department of Clinical and Experimental Medicine, Division of Surgery, Orthopedics and Oncology. Linköping University, Faculty of Medicine and Health Sciences.
Yeshiva Univ, NY 10033 USA.
Yeshiva Univ, NY 10033 USA.
Karolinska Inst, Sweden.
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2018 (English)In: Breast Cancer Research and Treatment, ISSN 0167-6806, E-ISSN 1573-7217, Vol. 168, no 1, p. 17-27Article in journal (Refereed) Published
Abstract [en]

Deregulated PI3K/mTOR signals can promote the growth of breast cancer and contribute to endocrine treatment resistance. This report aims to investigate raptor and its intracellular localization to further understand its role in ER-positive breast cancer. Raptor protein expression was evaluated by immunohistochemistry in 756 primary breast tumors from postmenopausal patients randomized to tamoxifen or no tamoxifen. In vitro, the MCF7 breast cancer cell line and tamoxifen-resistant MCF7 cells were studied to track the raptor signaling changes upon resistance, and raptor localization in ER alpha-positive cell lines was compared with that in ER alpha-negative cell lines. Raptor protein expression in the nucleus was high in ER/PgR-positive and HER2-negative tumors with low grade, features associated with the luminal A subtype. Presence of raptor in the nucleus was connected with ER alpha signaling, here shown by a coupled increase of ER alpha phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ER alpha-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ER alpha-positive, but not of ER-negative cells. Interestingly, raptor localized to the nucleus could still be seen in tamoxifen-resistant MCF7 cells. The clinical benefit from tamoxifen was inversely associated with an increase of nuclear raptor. High cytoplasmic raptor expression indicated worse prognosis on long-term follow-up. We present a connection between raptor localization to the nucleus and ER alpha-positive breast cancer, suggesting raptor as a player in stimulating the growth of the luminal A subtype and a possible target along with endocrine treatment.

Place, publisher, year, edition, pages
SPRINGER , 2018. Vol. 168, no 1, p. 17-27
Keywords [en]
mTOR; Estrogen receptor (ER) alpha; Tamoxifen; Endocrine resistance; Luminal A
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-147163DOI: 10.1007/s10549-017-4508-xISI: 000425747200003PubMedID: 29128895OAI: oai:DiVA.org:liu-147163DiVA, id: diva2:1199476
Note

Funding Agencies|Swedish Cancer Society; Region of Ostergotland; Cancer Society in Stockholm; King Gustav V Jubilee Clinical Research Foundation; National Cancer Institute (NCI); American Cancer Society; Atol Charitable Trust

Available from: 2018-04-20 Created: 2018-04-20 Last updated: 2018-05-28

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Bostner, JosefineNordenskjöld, BoStål, Olle
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