Dataset Information

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

ABSTRACT: In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E and p.R217C were not associated with breast cancer risk, the risk estimation for p.R217C was not very precise. To provide more conclusive evidence regarding the role of HOXB13 in breast cancer susceptibility, we here evaluated the association between HOXB13 mutations and increased breast cancer risk within 81 studies of the international Breast Cancer Association Consortium containing 68,521 invasive breast cancer patients and 54,865 controls. Both HOXB13 p.G84E and p.R217C did not associate with the development of breast cancer in European women, neither in the overall analysis (OR?=?1.035, 95% CI?=?0.859-1.246, P?=?0.718 and OR?=?0.798, 95% CI?=?0.482-1.322, P?=?0.381 respectively), nor in specific high-risk subgroups or breast cancer subtypes. Thus, although involved in breast cancer progression, HOXB13 is not a material breast cancer susceptibility gene.

SUBMITTER: Liu J

PROVIDER: S-EPMC7297796 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Liu Jingjing J Prager-van der Smissen Wendy J C WJC Collée J Margriet JM Bolla Manjeet K MK Wang Qin Q Michailidou Kyriaki K Dennis Joe J Ahearn Thomas U TU Aittomäki Kristiina K Ambrosone Christine B CB Andrulis Irene L IL Anton-Culver Hoda H Antonenkova Natalia N NN Arndt Volker V Arnold Norbert N Aronson Kristan J KJ Augustinsson Annelie A Auvinen Päivi P Becher Heiko H Beckmann Matthias W MW Behrens Sabine S Bermisheva Marina M Bernstein Leslie L Bogdanova Natalia V NV Bogdanova-Markov Nadja N Bojesen Stig E SE Brauch Hiltrud H Brenner Hermann H Briceno Ignacio I Brucker Sara Y SY Brüning Thomas T Burwinkel Barbara B Cai Qiuyin Q Cai Hui H Campa Daniele D Canzian Federico F Castelao Jose E JE Chang-Claude Jenny J Chanock Stephen J SJ Choi Ji-Yeob JY Christiaens Melissa M Clarke Christine L CL Couch Fergus J FJ Czene Kamila K Daly Mary B MB Devilee Peter P Dos-Santos-Silva Isabel I Dwek Miriam M Eccles Diana M DM Eliassen A Heather AH Fasching Peter A PA Figueroa Jonine J Flyger Henrik H Fritschi Lin L Gago-Dominguez Manuela M Gapstur Susan M SM García-Closas Montserrat M García-Sáenz José A JA Gaudet Mia M MM Giles Graham G GG Goldberg Mark S MS Goldgar David E DE Guénel Pascal P Haiman Christopher A CA Håkansson Niclas N Hall Per P Harrington Patricia A PA Hart Steven N SN Hartman Mikael M Hillemanns Peter P Hopper John L JL Hou Ming-Feng MF Hunter David J DJ Huo Dezheng D Ito Hidemi H Iwasaki Motoki M Jakimovska Milena M Jakubowska Anna A John Esther M EM Kaaks Rudolf R Kang Daehee D Keeman Renske R Khusnutdinova Elza E Kim Sung-Won SW Kraft Peter P Kristensen Vessela N VN Kurian Allison W AW Le Marchand Loic L Li Jingmei J Lindblom Annika A Lophatananon Artitaya A Luben Robert N RN Lubiński Jan J Mannermaa Arto A Manoochehri Mehdi M Manoukian Siranoush S Margolin Sara S Mariapun Shivaani S Matsuo Keitaro K Maurer Tabea T Mavroudis Dimitrios D Meindl Alfons A Menon Usha U Milne Roger L RL Muir Kenneth K Mulligan Anna Marie AM Neuhausen Susan L SL Nevanlinna Heli H Offit Kenneth K Olopade Olufunmilayo I OI Olson Janet E JE Olsson Håkan H Orr Nick N Park Sue K SK Peterlongo Paolo P Peto Julian J Plaseska-Karanfilska Dijana D Presneau Nadege N Rack Brigitte B Rau-Murthy Rohini R Rennert Gad G Rennert Hedy S HS Rhenius Valerie V Romero Atocha A Ruebner Matthias M Saloustros Emmanouil E Schmutzler Rita K RK Schneeweiss Andreas A Scott Christopher C Shah Mitul M Shen Chen-Yang CY Shu Xiao-Ou XO Simard Jacques J Sohn Christof C Southey Melissa C MC Spinelli John J JJ Tamimi Rulla M RM Tapper William J WJ Teo Soo H SH Terry Mary Beth MB Torres Diana D Truong Thérèse T Untch Michael M Vachon Celine M CM van Asperen Christi J CJ Wolk Alicja A Yamaji Taiki T Zheng Wei W Ziogas Argyrios A Ziv Elad E Torres-Mejía Gabriela G Dörk Thilo T Swerdlow Anthony J AJ Hamann Ute U Schmidt Marjanka K MK Dunning Alison M AM Pharoah Paul D P PDP Easton Douglas F DF Hooning Maartje J MJ Martens John W M JWM Hollestelle Antoinette A

Scientific reports 20200616 1

In breast cancer, high levels of homeobox protein Hox-B13 (HOXB13) have been associated with disease progression of ER-positive breast cancer patients and resistance to tamoxifen treatment. Since HOXB13 p.G84E is a prostate cancer risk allele, we evaluated the association between HOXB13 germline mutations and breast cancer risk in a previous study consisting of 3,270 familial non-BRCA1/2 breast cancer cases and 2,327 controls from the Netherlands. Although both recurrent HOXB13 mutations p.G84E ...[more]

PMID: 32546843

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Project description:BackgroundResistance to tamoxifen (TAM) frequently occurs in the treatment of estrogen receptor positive (ER+) breast cancer. Accumulating evidences indicate that transcription factor HOXB13 is of great significance in TAM resistance. However, the regulation of HOXB13 in TAM-resistant breast cancer remains largely unexplored. Here, we were interested in the potential effect of HBXIP, an oncoprotein involved in the acceleration of cancer progression, on the modulation of HOXB13 in TAM resistance of breast cancer.MethodsThe Kaplan-Meier plotter cancer database and GEO dataset were used to analyze the association between HBXIP expression and relapse-free survival. The correlation of HBXIP and HOXB13 in ER+ breast cancer was assessed by human tissue microarray. Immunoblotting analysis, qRT-PCR assay, immunofluorescence staining, Co-IP assay, ChIP assay, luciferase reporter gene assay, cell viability assay, and colony formation assay were performed to explore the possible molecular mechanism by which HBXIP modulates HOXB13. Cell viability assay, xenograft assay, and immunohistochemistry staining analysis were utilized to evaluate the effect of the HBXIP/HOXB13 axis on the facilitation of TAM resistance in vitro and in vivo.ResultsThe analysis of the Kaplan-Meier plotter and the GEO dataset showed that mono-TAM-treated breast cancer patients with higher HBXIP expression levels had shorter relapse-free survivals than patients with lower HBXIP expression levels. Overexpression of HBXIP induced TAM resistance in ER+ breast cancer cells. The tissue microarray analysis revealed a positive association between the expression levels of HBXIP and HOXB13 in ER+ breast cancer patients. HBXIP elevated HOXB13 protein level in breast cancer cells. Mechanistically, HBXIP prevented chaperone-mediated autophagy (CMA)-dependent degradation of HOXB13 via enhancement of HOXB13 acetylation at the lysine 277 residue, causing the accumulation of HOXB13. Moreover, HBXIP was able to act as a co-activator of HOXB13 to stimulate interleukin (IL)-6 transcription in the promotion of TAM resistance. Interestingly, aspirin (ASA) suppressed the HBXIP/HOXB13 axis by decreasing HBXIP expression, overcoming TAM resistance in vitro and in vivo.ConclusionsOur study highlights that HBXIP enhances HOXB13 acetylation to prevent HOXB13 degradation and co-activates HOXB13 in the promotion of TAM resistance of breast cancer. Therapeutically, ASA can serve as a potential candidate for reversing TAM resistance by inhibiting HBXIP expression.

Project description:BACKGROUND:It is unclear whether germline breast cancer susceptibility gene mutations affect breast cancer related outcomes. We wanted to evaluate mutation patterns in 20 breast cancer susceptibility genes and correlate the mutations with clinical characteristics to determine the effects of these germline mutations on breast cancer prognosis. METHODS:The study cohort included 480 ethnic Chinese individuals in Taiwan with at least one of the six clinical risk factors for hereditary breast cancer: family history of breast or ovarian cancer, young age of onset for breast cancer, bilateral breast cancer, triple negative breast cancer, both breast and ovarian cancer, and male breast cancer. PCR-enriched amplicon-sequencing on a next generation sequencing platform was used to determine the germline DNA sequences of all exons and exon-flanking regions of the 20 genes. Protein-truncating variants were identified as pathogenic. RESULTS:We detected a 13.5% carrier rate of pathogenic germline mutations, with BRCA2 being the most prevalent and the non-BRCA genes accounting for 38.5% of the mutation carriers. BRCA mutation carriers were more likely to be diagnosed of breast cancer with lymph node involvement (66.7% vs 42.6%; P?=?0.011), and had significantly worse breast cancer specific outcomes. The 5-year disease-free survival was 73.3% for BRCA mutation carriers and 91.1% for non-carriers (hazard ratio for recurrence or death 2.42, 95% CI 1.29-4.53; P?=?0.013). After adjusting for clinical prognostic factors, BRCA mutation remained an independent poor prognostic factor for cancer recurrence or death (adjusted hazard ratio 3.04, 95% CI 1.40-6.58; P?=?0.005). Non-BRCA gene mutation carriers did not exhibit any significant difference in cancer characteristics or outcomes compared to those without detected mutations. Among the risk factors for hereditary breast cancer, the odds of detecting a germline mutation increased significantly with having bilateral breast cancer (adjusted odds ratio 3.27, 95% CI 1.64-6.51; P?=?0.0008) or having more than one risk factor (odds ratio 2.07, 95% CI 1.22-3.51; P?=?0.007). CONCLUSIONS:Without prior knowledge of the mutation status, BRCA mutation carriers had more advanced breast cancer on initial diagnosis and worse cancer-related outcomes. Optimal approach to breast cancer treatment for BRCA mutation carriers warrants further investigation.

Dataset Information

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

Publications

Germline HOXB13 mutations p.G84E and p.R217C do not confer an increased breast cancer risk.

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