Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Breast Cancer Research and Treatment
Published in: Breast Cancer Research and Treatment 1/2018

Open Access 01-02-2018 | Preclinical study

Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer

Authors: Josefine Bostner, Anya Alayev, Adi Y. Berman, Tommy Fornander, Bo Nordenskjöld, Marina K. Holz, Olle Stål

Published in: Breast Cancer Research and Treatment | Issue 1/2018

Login to get access

Abstract

Purpose

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.

Methods

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 ERα-positive cell lines was compared with that in ERα-negative cell lines.

Results

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 ERα signaling, here shown by a coupled increase of ERα phosphorylation at S167 and S305 with accumulation of nuclear raptor. In addition, the expression of ERα-activated gene products correlated with nuclear raptor. Similarly, in vitro we observed raptor in the nucleus of ERα-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.

Conclusion

We present a connection between raptor localization to the nucleus and ERα-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.
Appendix
Available only for authorised users
Literature
1.
Musgrove EA, Sutherland RL (2009) Biological determinants of endocrine resistance in breast cancer. Nat Rev Cancer 9(9):631–643CrossRefPubMed
2.
3.
Miller TW, Hennessy BT, Gonzalez-Angulo AM, Fox EM, Mills GB, Chen H et al (2010) Hyperactivation of phosphatidylinositol-3 kinase promotes escape from hormone dependence in estrogen receptor-positive human breast cancer. J Clin Investig 120(7):2406–2413CrossRefPubMedPubMedCentral
4.
5.
Arriola Apelo SI, Lamming DW (2016) Rapamycin: an InhibiTOR of aging emerges from the soil of Easter Island. J Gerontol A 71(7):841–849CrossRef
6.
Hara K, Maruki Y, Long X, Yoshino K, Oshiro N, Hidayat S et al (2002) Raptor, a binding partner of target of rapamycin (TOR), mediates TOR action. Cell 110(2):177–189CrossRefPubMed
7.
Kim DH, Sarbassov DD, Ali SM, King JE, Latek RR, Erdjument-Bromage H et al (2002) mTOR interacts with raptor to form a nutrient-sensitive complex that signals to the cell growth machinery. Cell 110(2):163–175CrossRefPubMed
8.
Schalm SS, Blenis J (2002) Identification of a conserved motif required for mTOR signaling. Curr Biol 12(8):632–639CrossRefPubMed
9.
Schalm SS, Fingar DC, Sabatini DM, Blenis J (2003) TOS motif-mediated raptor binding regulates 4E-BP1 multisite phosphorylation and function. Curr Biol 13(10):797–806CrossRefPubMed
10.
Guertin DA, Stevens DM, Thoreen CC, Burds AA, Kalaany NY, Moffat J et al (2006) Ablation in mice of the mTORC components raptor, rictor, or mLST8 reveals that mTORC2 is required for signaling to Akt-FOXO and PKCalpha, but not S6K1. Dev Cell 11(6):859–871CrossRefPubMed
11.
Gangloff YG, Mueller M, Dann SG, Svoboda P, Sticker M, Spetz JF et al (2004) Disruption of the mouse mTOR gene leads to early postimplantation lethality and prohibits embryonic stem cell development. Mol Cell Biol 24(21):9508–9516CrossRefPubMedPubMedCentral
12.
Huang Z, Wu Y, Zhou X, Qian J, Zhu W, Shu Y et al (2015) Clinical efficacy of mTOR inhibitors in solid tumors: a systematic review. Future Oncol 11(11):1687–1699CrossRefPubMed
13.
Baselga J, Campone M, Piccart M, Burris HA 3rd, Rugo HS, Sahmoud T et al (2012) Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med 366(6):520–529CrossRefPubMed
14.
Maruani DM, Spiegel TN, Harris EN, Shachter AS, Unger HA, Herrero-Gonzalez S et al (2012) Estrogenic regulation of S6K1 expression creates a positive regulatory loop in control of breast cancer cell proliferation. Oncogene 31(49):5073–5080CrossRefPubMedPubMedCentral
15.
Yamnik RL, Digilova A, Davis DC, Brodt ZN, Murphy CJ, Holz MK (2009) S6 kinase 1 regulates estrogen receptor alpha in control of breast cancer cell proliferation. J Biol Chem 284(10):6361–6369CrossRefPubMed
16.
Yamnik RL, Holz MK (2010) mTOR/S6K1 and MAPK/RSK signaling pathways coordinately regulate estrogen receptor alpha serine 167 phosphorylation. FEBS Lett 584(1):124–128CrossRefPubMed
17.
Yu J, Henske EP (2006) Estrogen-induced activation of mammalian target of rapamycin is mediated via tuberin and the small GTPase Ras homologue enriched in brain. Cancer Res 66(19):9461–9466CrossRefPubMed
18.
Alayev A, Salamon RS, Berger SM, Schwartz NS, Cuesta R, Snyder RB et al (2016) mTORC1 directly phosphorylates and activates ERalpha upon estrogen stimulation. Oncogene 35(27):3535–3543CrossRefPubMed
19.
Karthik GM, Ma R, Lovrot J, Kis LL, Lindh C, Blomquist L et al (2015) mTOR inhibitors counteract tamoxifen-induced activation of breast cancer stem cells. Cancer Lett 367(1):76–87CrossRefPubMed
20.
Rutqvist LE, Johansson H, Stockholm Breast Cancer Study G (2007) Long-term follow-up of the randomized Stockholm trial on adjuvant tamoxifen among postmenopausal patients with early stage breast cancer. Acta Oncol 46(2):133–145CrossRefPubMed
21.
Beelen K, Zwart W, Linn SC (2012) Can predictive biomarkers in breast cancer guide adjuvant endocrine therapy? Nat Rev Clin Oncol 9(9):529–541CrossRefPubMed
22.
Manna S, Bostner J, Sun Y, Miller LD, Alayev A, Schwartz NS et al (2016) ERRalpha is a marker of tamoxifen response and survival in triple-negative breast cancer. Clin Cancer Res 22(6):1421–1431CrossRefPubMed
23.
Khoshnoud MR, Lofdahl B, Fohlin H, Fornander T, Stal O, Skoog L et al (2011) Immunohistochemistry compared to cytosol assays for determination of estrogen receptor and prediction of the long-term effect of adjuvant tamoxifen. Breast Cancer Res Treat 126(2):421–430CrossRefPubMed
24.
Bostner J, Skoog L, Fornander T, Nordenskjold B, Stal O (2010) Estrogen receptor-alpha phosphorylation at serine 305, nuclear p21-activated kinase 1 expression, and response to tamoxifen in postmenopausal breast cancer. Clin Cancer Res 16(5):1624–1633CrossRefPubMed
25.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM (2006) REporting recommendations for tumor MARKer prognostic studies (REMARK). Breast Cancer Res Treat 100(2):229–235CrossRefPubMed
26.
Bostner J, Karlsson E, Pandiyan MJ, Westman H, Skoog L, Fornander T et al (2013) Activation of Akt, mTOR, and the estrogen receptor as a signature to predict tamoxifen treatment benefit. Breast Cancer Res Treat 137(2):397–406CrossRefPubMed
27.
Kok M, Zwart W, Holm C, Fles R, Hauptmann M, Van’t Veer LJ et al (2011) PKA-induced phosphorylation of ERalpha at serine 305 and high PAK1 levels is associated with sensitivity to tamoxifen in ER-positive breast cancer. Breast Cancer Res Treat 125(1):1–12CrossRefPubMed
28.
Huderson BP, Duplessis TT, Williams CC, Seger HC, Marsden CG, Pouey KJ et al (2012) Stable inhibition of specific estrogen receptor alpha (ERalpha) phosphorylation confers increased growth, migration/invasion, and disruption of estradiol signaling in MCF-7 breast cancer cells. Endocrinology 153(9):4144–4159CrossRefPubMedPubMedCentral
29.
Anbalagan M, Rowan BG (2015) Estrogen receptor alpha phosphorylation and its functional impact in human breast cancer. Mol Cell Endocrinol 418(Pt 3):264–272CrossRefPubMed
30.
Wazir U, Newbold RF, Jiang WG, Sharma AK, Mokbel K (2013) Prognostic and therapeutic implications of mTORC1 and Rictor expression in human breast cancer. Oncol Rep 29(5):1969–1974CrossRefPubMed
31.
Bosch A, Li Z, Bergamaschi A, Ellis H, Toska E, Prat A et al (2015) PI3 K inhibition results in enhanced estrogen receptor function and dependence in hormone receptor-positive breast cancer. Sci Transl Med 7(283):283ra251CrossRef
32.
Le Romancer M, Poulard C, Cohen P, Sentis S, Renoir JM, Corbo L (2011) Cracking the estrogen receptor’s posttranslational code in breast tumors. Endocr Rev 32(5):597–622CrossRefPubMed
33.
Yang J, Singleton DW, Shaughnessy EA, Khan SA (2008) The F-domain of estrogen receptor-alpha inhibits ligand induced receptor dimerization. Mol Cell Endocrinol 295(1–2):94–100CrossRefPubMed
34.
Sharlow ER, Leimgruber S, Lira A, McConnell MJ, Norambuena A, Bloom GS et al (2016) A small molecule screen exposes mTOR signaling pathway involvement in radiation-induced apoptosis. ACS Chem Biol 11(5):1428–1437CrossRefPubMedPubMedCentral
Metadata
Title
Raptor localization predicts prognosis and tamoxifen response in estrogen receptor-positive breast cancer
Authors
Josefine Bostner
Anya Alayev
Adi Y. Berman
Tommy Fornander
Bo Nordenskjöld
Marina K. Holz
Olle Stål
Publication date
01-02-2018
Publisher
Springer US
Published in
Breast Cancer Research and Treatment / Issue 1/2018
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI
https://doi.org/10.1007/s10549-017-4508-x

Other articles of this Issue 1/2018

Breast Cancer Research and Treatment 1/2018 Go to the issue

Review

Breast-conserving surgery following neoadjuvant therapy-a systematic review on surgical outcomes

Brief Report

Speed of processing training in middle-aged and older breast cancer survivors (SOAR): results of a randomized controlled pilot

Epidemiology

Comparative effectiveness of incorporating a hypothetical DCIS prognostic marker into breast cancer screening

Clinical trial

Evaluation of applying IHC4 as a prognostic model in the translational study of Intergroup Exemestane Study (IES): PathIES

Brief Report

Validation of the 8th AJCC prognostic staging system for breast cancer in a population-based setting

Clinical trial

Measuring and understanding adherence in a home-based exercise intervention during chemotherapy for early breast cancer
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits