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2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

ABSTRACT: Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment Study (COGS) initiative. We carry out replication using Asian COGS samples (n=522, 53 events) and the Prospective Study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) study (n=315, 108 events). Rs4458204_A near CCL20 (2q36.3) is found to be associated with breast cancer-specific death at a genome-wide significant level (n=2,641, 440 events, combined allelic hazard ratio (HR)=1.81 (1.49-2.19); P for trend=1.90 × 10(-9)). Such survival-associated variants can represent ideal targets for tailored therapeutics, and may also enhance our current prognostic prediction capabilities.

SUBMITTER: Li J

PROVIDER: S-EPMC4082638 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

Li Jingmei J Lindström Linda S LS Foo Jia N JN Rafiq Sajjad S Schmidt Marjanka K MK Pharoah Paul D P PD Michailidou Kyriaki K Dennis Joe J Bolla Manjeet K MK Wang Qin Q Van 't Veer Laura J LJ Cornelissen Sten S Rutgers Emiel E Southey Melissa C MC Apicella Carmel C Dite Gillian S GS Hopper John L JL Fasching Peter A PA Haeberle Lothar L Ekici Arif B AB Beckmann Matthias W MW Blomqvist Carl C Muranen Taru A TA Aittomäki Kristiina K Lindblom Annika A Margolin Sara S Mannermaa Arto A Kosma Veli-Matti VM Hartikainen Jaana M JM Kataja Vesa V Chenevix-Trench Georgia G Phillips Kelly-Anne KA McLachlan Sue-Anne SA Lambrechts Diether D Thienpont Bernard B Smeets Ann A Wildiers Hans H Chang-Claude Jenny J Flesch-Janys Dieter D Seibold Petra P Rudolph Anja A Giles Graham G GG Baglietto Laura L Severi Gianluca G Haiman Christopher A CA Henderson Brian E BE Schumacher Fredrick F Le Marchand Loic L Kristensen Vessela V Alnæs Grethe I Grenaker GI Borresen-Dale Anne-Lise AL Nord Silje S Winqvist Robert R Pylkäs Katri K Jukkola-Vuorinen Arja A Grip Mervi M Andrulis Irene L IL Knight Julia A JA Glendon Gord G Tchatchou Sandrine S Devilee Peter P Tollenaar Robert R Seynaeve Caroline C Hooning Maartje M Kriege Mieke M Hollestelle Antoinette A van den Ouweland Ans A Li Yi Y Hamann Ute U Torres Diana D Ulmer Hans U HU Rüdiger Thomas T Shen Chen-Yang CY Hsiung Chia-Ni CN Wu Pei-Ei PE Chen Shou-Tung ST Teo Soo Hwang SH Taib Nur Aishah Mohd NA Har Yip Cheng C Fuang Ho Gwo G Matsuo Keitaro K Ito Hidemi H Iwata Hiroji H Tajima Kazuo K Kang Daehee D Choi Ji-Yeob JY Park Sue K SK Yoo Keun-Young KY Maishman Tom T Tapper William J WJ Dunning Alison A Shah Mitul M Luben Robert R Brown Judith J Khor Chiea Chuen CC Eccles Diana M DM Nevanlinna Heli H Easton Douglas D Humphreys Keith K Liu Jianjun J Hall Per P Czene Kamila K

Nature communications 20140617

Large population-based registry studies have shown that breast cancer prognosis is inherited. Here we analyse single-nucleotide polymorphisms (SNPs) of genes implicated in human immunology and inflammation as candidates for prognostic markers of breast cancer survival involving 1,804 oestrogen receptor (ER)-negative patients treated with chemotherapy (279 events) from 14 European studies in a prior large-scale genotyping experiment, which is part of the Collaborative Oncological Gene-environment ...[more]

PMID: 24937182

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Project description:BackgroundChemotherapy efficacy in early-stage hormone receptor-positive (HR+) breast cancer (BC) according to menopausal status needs a biological explanation.MethodsWe compared early-stage HR+ BC biological features before and after (neo)adjuvant chemotherapy or endocrine therapy (ET), and assessed oestrogen receptor (ER) pathway activity in both pre- and post-menopausal patients. The nCounter platform was used to detect gene expression levels.FindingsIn 106 post-menopausal patients with HR+/HER2-negative BC randomized to neoadjuvant chemotherapy or ET (letrozole+ribociclib), a total of 19 oestrogen-regulated genes, including progesterone receptor (PGR), were found downregulated in the ET-based arm-only. We confirmed this finding in an independent dataset of 20 letrozole-treated post-menopausal patients and found, conversely, an up-regulation of the same signature in HR+/HER2-negative MCF7 cell line treated with estradiol. PGR was found down-regulated by 2 weeks of ET+anti-HER2 therapy in pre-/post-menopausal patients with HR+/HER2-positive (HER2+) BC, while anti-HER2 therapy alone increased PGR expression in HR-negative/HER2+ BC. In 88 pre- and post-menopausal patients with newly diagnosed HR+/HER2-negative BC treated with chemotherapy, the 19 oestrogen-regulated genes were found significantly downregulated only in pre-menopausal patients. In progesterone receptor (PR)+/HER2-negative BC treated with neoadjuvant chemotherapy (n=40), tumours became PR-negative in 69.2% of pre-menopausal patients and 14.8% of post-menopausal patients (p=0.001). Finally, a mean decrease in PGR levels was only observed in pre-menopausal patients undergoing anti-HER2-based multi-agent chemotherapy.InterpretationChemotherapy reduces the expression of ER-regulated genes in pre-menopausal women suffering from hormone-dependent BC by supressing ovarian function. Further studies should test the value of chemotherapy in this patient population when ovarian function is suppressed by other methods.FundingInstituto de Salud Carlos III, Breast Cancer Now, the Breast Cancer Research Foundation, the American Association for Cancer Research, Fundació La Marató TV3, the European Union's Horizon 2020 Research and Innovation Programme, Pas a Pas, Save the Mama, Fundación Científica Asociación Española Contra el Cáncer, PhD4MDgrant of "Departament de Salut", exp SLT008/18/00122, Fundación SEOM and ESMO. Any views, opinions, findings, conclusions, or recommendations expressed in this material are those solely of the author(s).

Project description:IntroductionOestrogens can mediate some of their cell survival properties through a nongenomic mechanism that involves the mitogen-activated protein kinase (MAPK) pathway. The mechanism of this rapid signalling and its dependence on a membrane bound oestrogen receptor (ER), however, remains controversial. The role of G-protein-coupled receptor and epidermal growth factor (EGF) receptor in an ER-independent signalling pathway modulated by oestrogen was investigated.MethodsER-positive and ER-negative breast cancer cell lines (MCF-7 and SKBR3) and primary breast cancer cell cultures were used in this study. Cell proliferation was assessed using standard MTT assays. Protein and cAMP levels were detected by Western blotting and ELISA, respectively. Antigen localization was performed by immunocytochemistry, immunohistochemistry and immunofluorescence. Protein knockdown was achieved using small interfering RNA technologies.ResultsEGF and oestrogen, alone and in combination, induced cell proliferation and phosphorylation of MAPK proteins Raf and ERK (extracellular signal regulated kinase)1/2 in both ER-negative SKBR3 and ER-positive MCF-7 human breast cancer cell lines. Increased Raf phosphorylation was also observed in primary human breast cultures derived from ER-positive and ER-negative breast tumours. Oestrogen induced an increase in intracellular cAMP in ER-negative SKBR3 human breast cancer cells. Oestrogen-mediated cell growth and phosphorylation of MAPK was modified by the EGF receptor antagonist AG1478, the G-protein antagonist pertussis toxin, and the angiotensin II receptor antagonist saralasin. Knockdown of angiotensin II type 1 receptor (AT1) protein expression with small interfering RNA attenuated oestrogen-induced Raf phosphorylation in ER-negative cells. AT1 receptor was found to be expressed in the cell membrane of breast tumour epithelial cells.ConclusionThese findings provide evidence that, in breast cancer cells, oestrogen can signal through AT1 to activate early cell survival mechanisms in an ER-independent manner.

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2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

Publications

2q36.3 is associated with prognosis for oestrogen receptor-negative breast cancer patients treated with chemotherapy.

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