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 2023 EHA Congress 2023 ASCO Annual Meeting
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
Published in: Breast Cancer Research 1/2020

Open Access 01-12-2020 | Obesity | Research article

Effects of tumor-specific CAP1 expression and body constitution on clinical outcomes in patients with early breast cancer

Authors: Malin Bergqvist, Karin Elebro, Malte Sandsveden, Signe Borgquist, Ann H. Rosendahl

Published in: Breast Cancer Research | Issue 1/2020

Login to get access

Abstract

Background

Obesity induces molecular changes that may favor tumor progression and metastatic spread, leading to impaired survival outcomes in breast cancer. Adenylate cyclase-associated protein 1 (CAP1), an actin regulatory protein and functional receptor for the obesity-associated adipokine resistin, has been implicated with inferior cancer prognosis. Here, the objective was to investigate the interplay between body composition and CAP1 tumor expression regarding breast cancer outcome through long-term survival analyses.

Methods

Among 718 women with primary invasive breast cancer within the large population-based prospective Malmö Diet and Cancer Study, tumor-specific CAP1 levels were assessed following thorough antibody validation and immunohistochemical staining of tumor tissue microarrays. Antibody specificity and functional application validity were determined by CAP1 gene silencing, qRT-PCR, Western immunoblotting, and cell microarray immunostaining. Kaplan-Meier and multivariable Cox proportional hazard models were used to assess survival differences in terms of breast cancer-specific survival (BCSS) and overall survival (OS) according to body composition and CAP1 expression.

Results

Study participants were followed for up to 25 years (median 10.9 years), during which 239 deaths were observed. Patients with low CAP1 tumor expression were older at diagnosis, displayed anthropometric measurements indicating a higher adiposity status (wider waist and hip, higher body mass index and body fat percentage), and were more prone to have unfavorable tumor characteristics (higher histological grade, higher Ki67, and estrogen receptor (ER) negativity). Overall, patients with CAP1-low tumors had impaired BCSS (adjusted hazard ratio: HRadj = 0.52, 95% CI 0.31–0.88) and OS (HRadj = 0.64, 95% CI 0.44–0.92) compared with patients having high CAP1 tumor expression. Further, analyses stratified according to different anthropometric measures or ER status showed that the CAP1-associated survival outcomes were most pronounced among patients with low adiposity status or ER-positive disease.

Conclusions

Low CAP1 tumor expression was associated with higher body fatness and worse survival outcomes in breast cancer patients with effect modification by adiposity and ER status. CAP1 could be a novel marker for poorer survival outcome in leaner or ER-positive breast cancer patients, highlighting the need for considering body constitution in clinical decision making.
Appendix
Available only for authorised users
Literature
1.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMedCrossRef
2.
NORDCAN: cancer incidence, mortality, prevalence and survival in the Nordic countries, Version 8.2. 2019 [cited 01.04.19].
3.
Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K, et al. Body fatness and cancer--viewpoint of the IARC Working Group. N Engl J Med. 2016;375(8):794–8.PubMedPubMedCentralCrossRef
4.
Cancer Intelligence Team PID, Cancer Research UK. When could overweight and obesity overtake smoking as the biggest cause of cancer in the UK 2018.
5.
Munsell MF, Sprague BL, Berry DA, Chisholm G, Trentham-Dietz A. Body mass index and breast cancer risk according to postmenopausal estrogen-progestin use and hormone receptor status. Epidemiol Rev. 2014;36:114–36.PubMedPubMedCentralCrossRef
6.
Yang XR, Chang-Claude J, Goode EL, Couch FJ, Nevanlinna H, Milne RL, et al. Associations of breast cancer risk factors with tumor subtypes: a pooled analysis from the Breast Cancer Association Consortium studies. J Natl Cancer Inst. 2011;103(3):250–63.PubMedCrossRef
7.
Neuhouser ML, Aragaki AK, Prentice RL, Manson JE, Chlebowski R, Carty CL, et al. Overweight, obesity, and postmenopausal invasive breast cancer risk: a secondary analysis of the Women’s Health Initiative randomized clinical trials. JAMA Oncol. 2015;1(5):611–21.PubMedPubMedCentralCrossRef
8.
Ewertz M, Jensen MB, Gunnarsdottir KA, Hojris I, Jakobsen EH, Nielsen D, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol. 2011;29(1):25–31.PubMedCrossRef
9.
Seo BR, Bhardwaj P, Choi S, Gonzalez J, Andresen Eguiluz RC, Wang K, et al. Obesity-dependent changes in interstitial ECM mechanics promote breast tumorigenesis. Sci Transl Med. 2015;7(301):301ra130.PubMedPubMedCentralCrossRef
10.
Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71(7):2455–65.PubMedCrossRef
11.
Sadashiv TS, Paul BN, Kumar S, Chandra A, Dhananjai S, et al. Over expression of resistin in adipose tissue of the obese induces insulin resistance. World J Diabetes. 2012;3(7):135–41.PubMedPubMedCentralCrossRef
12.
Steppan CM, Bailey ST, Bhat S, Brown EJ, Banerjee RR, Wright CM, et al. The hormone resistin links obesity to diabetes. Nature. 2001;409(6818):307–12.PubMedCrossRef
13.
Gong WJ, Zheng W, Xiao L, Tan LM, Song J, Li XP, et al. Circulating resistin levels and obesity-related cancer risk: a meta-analysis. Oncotarget. 2016;7(36):57694–704.PubMedPubMedCentralCrossRef
14.
Assiri AM, Kamel HF, Hassanien MF. Resistin, visfatin, adiponectin, and leptin: risk of breast cancer in pre- and postmenopausal Saudi females and their possible diagnostic and predictive implications as novel biomarkers. Dis Markers. 2015;2015:253519.PubMedPubMedCentralCrossRef
15.
Rosendahl AH, Bergqvist M, Lettiero B, Kimbung S, Borgquist S. Adipocytes and obesity-related conditions jointly promote breast cancer cell growth and motility: associations with CAP1 for prognosis. Front Endocrinol. 2018;9:689.CrossRef
16.
Lee YC, Chen YJ, Wu CC, Lo S, Hou MF, Yuan SS. Resistin expression in breast cancer tissue as a marker of prognosis and hormone therapy stratification. Gynecol Oncol. 2012;125(3):742–50.PubMedCrossRef
17.
Lee S, Lee HC, Kwon YW, Lee SE, Cho Y, Kim J, et al. Adenylyl cyclase-associated protein 1 is a receptor for human resistin and mediates inflammatory actions of human monocytes. Cell Metab. 2014;19(3):484–97.PubMedPubMedCentralCrossRef
18.
Fedor-Chaiken M, Deschenes RJ, Broach JR. SRV2, a gene required for RAS activation of adenylate cyclase in yeast. Cell. 1990;61(2):329–40.PubMedCrossRef
19.
Yu G, Swiston J, Young D. Comparison of human CAP and CAP2, homologs of the yeast adenylyl cyclase-associated proteins. J Cell Sci. 1994;107(Pt 6):1671–8.PubMedCrossRef
20.
Xie S, Shen C, Tan M, Li M, Song X, Wang C. Systematic analysis of gene expression alterations and clinical outcomes of adenylate cyclase-associated protein in cancer. Oncotarget. 2017;8(16):27216–39.PubMedPubMedCentralCrossRef
21.
Bertling E, Hotulainen P, Mattila PK, Matilainen T, Salminen M, Lappalainen P. Cyclase-associated protein 1 (CAP1) promotes cofilin-induced actin dynamics in mammalian nonmuscle cells. Mol Biol Cell. 2004;15(5):2324–34.PubMedPubMedCentralCrossRef
22.
Yamaguchi H, Condeelis J. Regulation of the actin cytoskeleton in cancer cell migration and invasion. Biochim Biophys Acta. 2007;1773(5):642–52.PubMedCrossRef
23.
Hua M, Yan S, Deng Y, Xi Q, Liu R, Yang S, et al. CAP1 is overexpressed in human epithelial ovarian cancer and promotes cell proliferation. Int J Mol Med. 2015;35(4):941–9.PubMedPubMedCentralCrossRef
24.
Fan YC, Cui CC, Zhu YS, Zhang L, Shi M, Yu JS, et al. Overexpression of CAP1 and its significance in tumor cell proliferation, migration and invasion in glioma. Oncol Rep. 2016;36(3):1619–25.PubMedCrossRef
25.
Liu Y, Cui X, Hu B, Lu C, Huang X, Cai J, et al. Upregulated expression of CAP1 is associated with tumor migration and metastasis in hepatocellular carcinoma. Pathol Res Pract. 2014;210(3):169–75.PubMedCrossRef
26.
Berglund G, Elmstahl S, Janzon L, Larsson SA. The Malmo Diet and Cancer Study. Design and feasibility. J Intern Med. 1993;233(1):45–51.PubMedCrossRef
27.
Manjer J, Carlsson S, Elmstahl S, Gullberg B, Janzon L, Lindstrom M, et al. The Malmo Diet and Cancer Study: representativity, cancer incidence and mortality in participants and non-participants. Eur J Cancer Prev. 2001;10(6):489–99.PubMedCrossRef
28.
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991;19(5):403–10.PubMedCrossRef
29.
Borgquist S, Djerbi S, Ponten F, Anagnostaki L, Goldman M, Gaber A, et al. HMG-CoA reductase expression in breast cancer is associated with a less aggressive phenotype and influenced by anthropometric factors. Int J Cancer. 2008;123(5):1146–53.PubMedCrossRef
30.
Borgquist S, Anagnostaki L, Jirstrom K, Landberg G, Manjer J. Breast tumours following combined hormone replacement therapy express favourable prognostic factors. Int J Cancer. 2007;120(10):2202–7.PubMedCrossRef
31.
32.
33.
McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M, Clark GM, et al. Reporting recommendations for tumor marker prognostic studies (REMARK). J Natl Cancer Inst. 2005;97(16):1180–4.PubMedCrossRef
34.
Tan M, Song X, Zhang G, Peng A, Li X, Li M, et al. Overexpression of adenylate cyclase-associated protein 1 is associated with metastasis of lung cancer. Oncol Rep. 2013;30(4):1639–44.PubMedCrossRef
35.
Lundgren K, Brown M, Pineda S, Cuzick J, Salter J, Zabaglo L, et al. Effects of cyclin D1 gene amplification and protein expression on time to recurrence in postmenopausal breast cancer patients treated with anastrozole or tamoxifen: a TransATAC study. Breast Cancer Res. 2012;14(2):R57.PubMedPubMedCentralCrossRef
36.
Rudas M, Lehnert M, Huynh A, Jakesz R, Singer C, Lax S, et al. Cyclin D1 expression in breast cancer patients receiving adjuvant tamoxifen-based therapy. Clin Cancer Res. 2008;14(6):1767–74.PubMedCrossRef
37.
38.
Liu X, Yao N, Qian J, Huang H. High expression and prognostic role of CAP1 and CtBP2 in breast carcinoma: associated with E-cadherin and cell proliferation. Med Oncol. 2014;31(3):878.PubMedCrossRef
39.
Yu XF, Ni QC, Chen JP, Xu JF, Jiang Y, Yang SY, et al. Knocking down the expression of adenylate cyclase-associated protein 1 inhibits the proliferation and migration of breast cancer cells. Exp Mol Pathol. 2014;96(2):188–94.PubMedCrossRef
40.
Xie S, Liu Y, Li X, Tan M, Wang C, Field J, et al. Phosphorylation of the cytoskeletal protein CAP1 regulates non-small cell lung cancer survival and proliferation by GSK3beta. J Cancer. 2018;9(16):2825–33.PubMedPubMedCentralCrossRef
41.
Zhou GL, Zhang H, Wu H, Ghai P, Field J. Phosphorylation of the cytoskeletal protein CAP1 controls its association with cofilin and actin. J Cell Sci. 2014;127(Pt 23):5052–65.PubMedPubMedCentral
42.
Zhang H, Zhou GL. CAP1 (cyclase-associated protein 1) exerts distinct functions in the proliferation and metastatic potential of breast cancer cells mediated by ERK. Sci Rep. 2016;6:25933.PubMedPubMedCentralCrossRef
Metadata
Title
Effects of tumor-specific CAP1 expression and body constitution on clinical outcomes in patients with early breast cancer
Authors
Malin Bergqvist
Karin Elebro
Malte Sandsveden
Signe Borgquist
Ann H. Rosendahl
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2020
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-020-01307-5

Other articles of this Issue 1/2020

Breast Cancer Research 1/2020 Go to the issue

Research article

PRKCQ inhibition enhances chemosensitivity of triple-negative breast cancer by regulating Bim

Research article

Immune parameters associated with survival in metaplastic breast cancer

Research article

Simultaneous targeting of HER family pro-survival signaling with Pan-HER antibody mixture is highly effective in TNBC: a preclinical trial with PDXs

Research article

Inter-tumor genomic heterogeneity of breast cancers: comprehensive genomic profile of primary early breast cancers and relapses

Research article

A window-of-opportunity trial of the CXCR1/2 inhibitor reparixin in operable HER-2-negative breast cancer

Research article

Progesterone receptor membrane component 1 regulates lipid homeostasis and drives oncogenic signaling resulting in breast cancer progression
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