Top

Published in:

Open Access 01-12-2016 | Research article

Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy

Authors: Takayuki Ueno, Shigehira Saji, Masahiro Sugimoto, Norikazu Masuda, Katsumasa Kuroi, Nobuaki Sato, Hiroyuki Takei, Yutaka Yamamoto, Shinji Ohno, Hiroko Yamashita, Kazufumi Hisamatsu, Kenjiro Aogi, Hiroji Iwata, Shigeru Imoto, Hironobu Sasano, Masakazu Toi

Published in: BMC Cancer | Issue 1/2016

Abstract

Background

Neoadjuvant endocrine therapy (NAE) has been employed to improve surgical outcomes for hormone receptor-positive breast cancers in postmenopausal women. Endocrine responsiveness is estimated by expressions of hormone receptors, but its heterogeneity has been recognized. Autophagy is an evolutionally conserved process associated with cell survival and cell death and has been implicated in cancer treatment.

Methods

In order to examine the possible association between autophagy and response to endocrine therapy, we evaluated the status of autophagy-associated markers, beclin 1 and LC3, and apoptosis-associated markers, TUNEL and M30, in pre- and post-treatment specimens from 71 patients in a multicenter prospective study of neoadjuvant exemestane (JFMC34-0601).

Results

Immunoreactivity of the autophagy-associated markers, beclin 1 and LC3, in carcinoma cells increased in 14 % and 52 % of the patients, respectively, following the exemestane treatment. These increases were statistically significant (beclin 1, p = 0.016, N = 49; LC3, p < 0.0001, N = 33). The status of M30 immunoreactivity decreased (p = 0.008, N = 47) and TUNEL remained unchanged (N = 53). In addition, tumors with pre-treatment stromal beclin 1 immunoreactivity revealed poor clinical and pathological responses compared with those without stromal beclin 1 immunoreactivity (25 % vs 67 % for clinical response, p = 0.011, N = 51; 0 % vs 41 % for pathological response, p = 0.0081, N = 49). Tumors with positive pre-treatment stromal beclin 1 had a higher baseline Ki-67 labeling index (both hot spot and overall average) than those without (p = 0.042 and 0.0075, respectively, N = 53). Results of logistic regression analyses revealed that stromal beclin 1 was a predictor for clinical and pathological responses while ER, PR, Ki-67, and stromal LC3 expressions were not.

Conclusions

Results of our present study demonstrated that beclin 1 and LC3 immunoreactivity increased in carcinoma cells following exemestane treatment and that the status of pre-treatment stromal beclin 1 is associated with higher carcinoma cell proliferation and poor clinical and pathological responses to NAE.

Trial registration

UMIN C000000345 (2006/03/06)

Available only for authorised users

Chia YH, Ellis MJ, Ma CX. Neoadjuvant endocrine therapy in primary breast cancer: indications and use as a research tool. Br J Cancer. 2010;103(6):759–64.CrossRefPubMedPubMedCentral

Ellis MJ, Suman VJ, Hoog J, Lin L, Snider J, Prat A, Parker JS, Luo J, Deschryver K, Allred DC, et al. Randomized Phase II Neoadjuvant Comparison Between Letrozole, Anastrozole, and Exemestane for Postmenopausal Women With Estrogen Receptor-Rich Stage 2 to 3 Breast Cancer: Clinical and Biomarker Outcomes and Predictive Value of the Baseline PAM50-Based Intrinsic Subtype--ACOSOG Z1031. J Clin Oncol. 2011;29(17):2342–9.CrossRefPubMedPubMedCentral

Dowsett M, Smith IE, Ebbs SR, Dixon JM, Skene A, Griffith C, Boeddinghaus I, Salter J, Detre S, Hills M, et al. Short-term changes in Ki-67 during neoadjuvant treatment of primary breast cancer with anastrozole or tamoxifen alone or combined correlate with recurrence-free survival. Clin Cancer Res. 2005;11(2 Pt 2):951s–8s.PubMed

White E. Deconvoluting the context-dependent role for autophagy in cancer. Nat Rev Cancer. 2012;12(6):401–10.CrossRefPubMedPubMedCentral

Qu X, Yu J, Bhagat G, Furuya N, Hibshoosh H, Troxel A, Rosen J, Eskelinen EL, Mizushima N, Ohsumi Y, et al. Promotion of tumorigenesis by heterozygous disruption of the beclin 1 autophagy gene. J Clin Invest. 2003;112(12):1809–20.CrossRefPubMedPubMedCentral

Liang XH, Jackson S, Seaman M, Brown K, Kempkes B, Hibshoosh H, Levine B. Induction of autophagy and inhibition of tumorigenesis by beclin 1. Nature. 1999;402(6762):672–6.CrossRefPubMed

Lock R, Roy S, Kenific CM, Su JS, Salas E, Ronen SM, Debnath J. Autophagy facilitates glycolysis during Ras-mediated oncogenic transformation. Mol Biol Cell. 2011;22(2):165–78.CrossRefPubMedPubMedCentral

Wei H, Wei S, Gan B, Peng X, Zou W, Guan JL. Suppression of autophagy by FIP200 deletion inhibits mammary tumorigenesis. Genes Dev. 2011;25(14):1510–27.CrossRefPubMedPubMedCentral

Toi M, Saji S, Masuda N, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, Hisamatsu K et al. Ki67 index changes, pathological response and clinical benefits in primary breast cancer patients treated with 24 weeks of aromatase inhibition. Cancer Sci. 2011;102(4):858–65.CrossRefPubMed

10.

Ueno T, Masuda N, Yamanaka T, Saji S, Kuroi K, Sato N, Takei H, Yamamoto Y, Ohno S, Yamashita H, et al. Evaluating the 21-gene assay Recurrence Score as a predictor of clinical response to 24 weeks of neoadjuvant exemestane in estrogen receptor-positive breast cancer. Int J Clin Oncol. 2013.

11.

Miller WR, White S, Dixon JM, Murray J, Renshaw L, Anderson TJ. Proliferation, steroid receptors and clinical/pathological response in breast cancer treated with letrozole. Br J Cancer. 2006;94(7):1051–6.CrossRefPubMedPubMedCentral

12.

Dowsett M, Nielsen TO, A’Hern R, Bartlett J, Coombes RC, Cuzick J, Ellis M, Henry NL, Hugh JC, Lively T, et al. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011;103(22):1656–64.CrossRefPubMedPubMedCentral

13.

Harvey JM, Clark GM, Osborne CK, Allred DC. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol. 1999;17(5):1474–81.CrossRefPubMed

14.

Amaral C, Borges M, Melo S, da Silva ET, Correia-da-Silva G, Teixeira N. Apoptosis and autophagy in breast cancer cells following exemestane treatment. PLoS One. 2012;7(8), e42398.CrossRefPubMedPubMedCentral

15.

Amaral C, Varela C, Azevedo M, da Silva ET, Roleira FM, Chen S, Correia-da-Silva G, Teixeira N. Effects of steroidal aromatase inhibitors on sensitive and resistant breast cancer cells: aromatase inhibition and autophagy. J Steroid Biochem Mol Biol. 2013;135:51–9.CrossRefPubMed

16.

Cook KL, Shajahan AN, Warri A, Jin L, Hilakivi-Clarke LA, Clarke R. Glucose-Regulated Protein 78 Controls Cross-talk between Apoptosis and Autophagy to Determine Antiestrogen Responsiveness. Cancer Res. 2012;72(13):3337–49.CrossRefPubMedPubMedCentral

17.

Cook KL, Clarke PA, Parmar J, Hu R, Schwartz-Roberts JL, Abu-Asab M, Warri A, Baumann WT, Clarke R. Knockdown of estrogen receptor-alpha induces autophagy and inhibits antiestrogen-mediated unfolded protein response activation, promoting ROS-induced breast cancer cell death. FASEB J. 2014;28(9):3891–905.CrossRefPubMedPubMedCentral

18.

Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, Zhou J, Wang C, Pavlides S, Martinez-Cantarin MP, Capozza F, et al. Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFkappaB activation in the tumor stromal microenvironment. Cell Cycle. 2010;9(17):3515–33.CrossRefPubMedPubMedCentral

19.

Qian N, Ueno T, Kawaguchi-Sakita N, Kawashima M, Yoshida N, Mikami Y, Wakasa T, Shintaku M, Tsuyuki S, Inamoto T, et al. Prognostic significance of tumor/stromal caveolin-1 expression in breast cancer patients. Cancer Sci. 2011;102(8):1590–6.CrossRefPubMed

20.

Witkiewicz AK, Dasgupta A, Sotgia F, Mercier I, Pestell RG, Sabel M, Kleer CG, Brody JR, Lisanti MP. An absence of stromal caveolin-1 expression predicts early tumor recurrence and poor clinical outcome in human breast cancers. Am J Pathol. 2009;174(6):2023–34.CrossRefPubMedPubMedCentral

21.

Rogov V, Dotsch V, Johansen T, Kirkin V. Interactions between autophagy receptors and ubiquitin-like proteins form the molecular basis for selective autophagy. Mol Cell. 2014;53(2):167–78.CrossRefPubMed

22.

Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.CrossRefPubMedPubMedCentral

23.

Chang J, Powles TJ, Allred DC, Ashley SE, Makris A, Gregory RK, Osborne CK, Dowsett M. Prediction of clinical outcome from primary tamoxifen by expression of biologic markers in breast cancer patients. Clin Cancer Res. 2000;6(2):616–21.PubMed

Title: Clinical significance of the expression of autophagy-associated marker, beclin 1, in breast cancer patients who received neoadjuvant endocrine therapy
Authors: Takayuki Ueno
Shigehira Saji
Masahiro Sugimoto
Norikazu Masuda
Katsumasa Kuroi
Nobuaki Sato
Hiroyuki Takei
Yutaka Yamamoto
Shinji Ohno
Hiroko Yamashita
Kazufumi Hisamatsu
Kenjiro Aogi
Hiroji Iwata
Shigeru Imoto
Hironobu Sasano
Masakazu Toi
Publication date: 01-12-2016
Publisher: BioMed Central
Published in: BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-016-2270-9

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

Keynote webinar | Spotlight on sleep in brain health

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

Trial registration

Please log in to get access to this content

Other articles of this Issue 1/2016

Molecular features of the cytotoxicity of an NHE inhibitor: Evidence of mitochondrial alterations, ROS overproduction and DNA damage

Antitumor effects of cecropin B-LHRH’ on drug-resistant ovarian and endometrial cancer cells

Benchmarking trial between France and Australia comparing management of primary rectal cancer beyond TME and locally recurrent rectal cancer (PelviCare Trial): rationale and design

Overexpression of UNC5B in bladder cancer cells inhibits proliferation and reduces the volume of transplantation tumors in nude mice

Frequency of EGFR T790M mutation and multimutational profiles of rebiopsy samples from non-small cell lung cancer developing acquired resistance to EGFR tyrosine kinase inhibitors in Japanese patients

SOX2 expression is associated with a cancer stem cell state and down-regulation of CDX2 in colorectal cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer