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Breast Cancer Research
Published in: Breast Cancer Research 1/2017

Open Access 01-12-2017 | Research article

Roles of BCCIP deficiency in mammary tumorigenesis

Authors: Roberto Droz-Rosario, Huimei Lu, Jingmei Liu, Ning-Ang Liu, Shridar Ganesan, Bing Xia, Bruce G. Haffty, Zhiyuan Shen

Published in: Breast Cancer Research | Issue 1/2017

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Abstract

Background

Dysregulated DNA repair and cell proliferation controls are essential driving forces in mammary tumorigenesis. BCCIP was originally identified as a BRCA2 and CDKN1A interacting protein that has been implicated in maintenance of genomic stability, cell cycle regulation, and microtubule dynamics. The aims of this study were to determine whether BCCIP deficiency contributes to mammary tumorigenesis, especially for a subset of breast cancers with 53BP1 abnormality, and to reveal the mechanistic implications of BCCIP in breast cancer interventions.

Methods

We analyzed the BCCIP protein level in 470 cases of human breast cancer to determine the associations between BCCIP and 53BP1, p53, and subtypes of breast cancer. We further constructed a unique BCCIP knockdown mouse model to determine whether a partial BCCIP deficiency leads to spontaneous breast cancer formation.

Results

We found that the BCCIP protein level is downregulated in 49% of triple-negative breast cancer and 25% of nontriple-negative breast cancer. The downregulation of BCCIP is mutually exclusive with p53 mutations but concurrent with 53BP1 loss in triple-negative breast cancer. In a K14-Cre-mediated conditional BCCIP knockdown mouse model, we found that BCCIP downregulation causes a formation of benign modules in the mammary glands, resembling the epidermal inclusion cyst of the breast. However, the majority of these benign lesions remain indolent, and only ~ 10% of them evolve into malignant tumors after a long latency. This tumor progression is associated with a loss of 53BP1 and p16 expression. BCCIP knockdown did not alter the latency of mammary tumor formation induced by conditional Trp53 deletion.

Conclusions

Our data suggest a confounding role of BCCIP deficiency in modulating breast cancer development by enhancing tumor initiation but hindering progression. Furthermore, secondary genetic alternations may overcome the progression suppression imposed by BCCIP deficiency through a synthetic viability mechanism.
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Literature
1.
Curtin NJ. DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer. 2012;12(12):801–17.CrossRefPubMed
2.
3.
4.
Sorlie T, Perou CM, Tibshirani R, Aas T, Geisler S, Johnsen H, Hastie T, Eisen MB, van de Rijn M, Jeffrey SS, et al. Gene expression patterns of breast carcinomas distinguish tumor subclasses with clinical implications. Proc Natl Acad Sci U S A. 2001;98(19):10869–74.CrossRefPubMedPubMedCentral
5.
Calza S, Hall P, Auer G, Bjohle J, Klaar S, Kronenwett U, Liu ET, Miller L, Ploner A, Smeds J, et al. Intrinsic molecular signature of breast cancer in a population-based cohort of 412 patients. Breast Cancer Res. 2006;8(4):R34.CrossRefPubMedPubMedCentral
6.
Kreike B, van Kouwenhove M, Horlings H, Weigelt B, Peterse H, Bartelink H, van de Vijver MJ. Gene expression profiling and histopathological characterization of triple-negative/basal-like breast carcinomas. Breast Cancer Res. 2007;9(5):R65.CrossRefPubMedPubMedCentral
7.
8.
Evers B, Jonkers J. Mouse models of BRCA1 and BRCA2 deficiency: past lessons, current understanding and future prospects. Oncogene. 2006;25(43):5885–97.CrossRefPubMed
9.
Liu X, Holstege H, van der Gulden H, Treur-Mulder M, Zevenhoven J, Velds A, Kerkhoven RM, van Vliet MH, Wessels LF, Peterse JL, et al. Somatic loss of BRCA1 and p53 in mice induces mammary tumors with features of human BRCA1-mutated basal-like breast cancer. Proc Natl Acad Sci U S A. 2007;104(29):12111–6.CrossRefPubMedPubMedCentral
10.
Jonkers J, Meuwissen R, van der Gulden H, Peterse H, van der Valk M, Berns A. Synergistic tumor suppressor activity of BRCA2 and p53 in a conditional mouse model for breast cancer. Nat Genet. 2001;29(4):418–25.CrossRefPubMed
11.
Cheung AM, Elia A, Tsao MS, Done S, Wagner KU, Hennighausen L, Hakem R, Mak TW. Brca2 deficiency does not impair mammary epithelium development but promotes mammary adenocarcinoma formation in p53(+/–) mutant mice. Cancer Res. 2004;64(6):1959–65.CrossRefPubMed
12.
Liu J, Yuan Y, Huan J, Shen Z. Inhibition of breast and brain cancer cell growth by BCCIPalpha, an evolutionarily conserved nuclear protein that interacts with BRCA2. Oncogene. 2001;20(3):336–45.CrossRefPubMed
13.
Mao N, Zhou Q, Kojic M, Perez-Martin J, Holloman WK. Ortholog of BRCA2-interacting protein BCCIP controls morphogenetic responses during DNA replication stress in Ustilago maydis. DNA Repair (Amst). 2007;6(11):1651–60.CrossRef
14.
Meng X, Liu J, Shen Z. Inhibition of G1 to S cell cycle progression by BCCIP beta. Cell Cycle. 2004;3(3):343–8.CrossRefPubMed
15.
Meng X, Lu H, Shen Z. BCCIP functions through p53 to regulate the expression of p21Waf1/Cip1. Cell Cycle. 2004;3(11):1457–62.CrossRefPubMed
16.
Lu H, Guo X, Meng X, Liu J, Allen C, Wray J, Nickoloff JA, Shen Z. The BRCA2-interacting protein BCCIP functions in RAD51 and BRCA2 focus formation and homologous recombinational repair. Mol Cell Biol. 2005;25(5):1949–57.CrossRefPubMedPubMedCentral
17.
Lu H, Yue J, Meng X, Nickoloff JA, Shen Z. BCCIP regulates homologous recombination by distinct domains and suppresses spontaneous DNA damage. Nucleic Acids Res. 2007;35(21):7160–70.CrossRefPubMedPubMedCentral
18.
19.
20.
Wray J, Liu J, Nickoloff JA, Shen Z. Distinct RAD51 associations with RAD52 and BCCIP in response to DNA damage and replication stress. Cancer Res. 2008;68(8):2699–707.CrossRefPubMedPubMedCentral
21.
Wyler E, Wandrey F, Badertscher L, Montellese C, Alper D, Kutay U. The beta-isoform of the BRCA2 and CDKN1A(p21)-interacting protein (BCCIP) stabilizes nuclear RPL23/uL14. FEBS Lett. 2014;588(20):3685–91.CrossRefPubMed
22.
Kelso AA, Goodson SD, Watts LE, Ledford LL, Waldvogel SM, Diehl JN, Shah SB, Say AF, White JD, Sehorn MG. The beta-isoform of BCCIP promotes ADP release from the RAD51 presynaptic filament and enhances homologous DNA pairing. Nucleic Acids Res. 2017;45:711–25.
23.
Chakrabarti SR, Sood R, Ganguly S, Bohlander S, Shen Z, Nucifora G. Modulation of TEL transcription activity by interaction with the ubiquitin-conjugating enzyme UBC9. Proc Natl Acad Sci U S A. 1999;96(13):7467–72.CrossRefPubMedPubMedCentral
24.
Huang YY, Dai L, Gaines D, Droz-Rosario R, Lu H, Liu J, Shen Z. BCCIP suppresses tumor initiation but is required for tumor progression. Cancer Res. 2013;73(23):7122–33.CrossRefPubMedPubMedCentral
25.
Meng X, Liu J, Shen Z. Genomic structure of the human BCCIP gene and its expression in cancer. Gene. 2003;302(1–2):139–46.CrossRefPubMed
26.
Ba Q, Li X, Huang C, Li J, Fu Y, Chen P, Duan J, Hao M, Zhang Y, Li J, et al. BCCIPbeta modulates the ribosomal and extraribosomal function of S7 through a direct interaction. J Mol Cell Biol. 2017;9(3):209–19.CrossRefPubMed
27.
Huhn SC, Liu J, Ye C, Lu H, Jiang X, Feng X, Ganesan S, White E, Shen Z. Regulation of spindle integrity and mitotic fidelity by BCCIP. Oncogene. 2017;36(33):4750–66.CrossRefPubMedPubMedCentral
28.
Meng X, Yue J, Liu Z, Shen Z. Abrogation of the transactivation activity of p53 by BCCIP down-regulation. J Biol Chem. 2007;282(3):1570–6.CrossRefPubMed
29.
Rewari A, Lu H, Parikh R, Yang Q, Shen Z, Haffty BG. BCCIP as a prognostic marker for radiotherapy of laryngeal cancer. Radiother Oncol. 2009;90(2):183–8.CrossRefPubMed
30.
Lu H, Huang YY, Mehrotra S, Droz-Rosario R, Liu J, Bhaumik M, White E, Shen Z. Essential roles of BCCIP in mouse embryonic development and structural stability of chromosomes. PLoS Genet. 2011;7(9):e1002291.CrossRefPubMedPubMedCentral
31.
Bouwman P, Drost R, Klijn C, Pieterse M, van der Gulden H, Song JY, Szuhai K, Jonkers J. Loss of p53 partially rescues embryonic development of Palb2 knockout mice but does not foster haploinsufficiency of Palb2 in tumour suppression. J Pathol. 2011;224(1):10–21.CrossRefPubMed
32.
Hakem R, de la Pompa JL, Elia A, Potter J, Mak TW. Partial rescue of Brca1 (5-6) early embryonic lethality by p53 or p21 null mutation. Nat Genet. 1997;16(3):298–302.CrossRefPubMed
33.
Bonache S, Gutierrez-Enriquez S, Tenes A, Masas M, Balmana J, Diez O. Mutation analysis of the BCCIP gene for breast cancer susceptibility in breast/ovarian cancer families. Gynecol Oncol. 2013;131(2):460–3.CrossRefPubMed
34.
Huang YY, Lu H, Liu S, Droz-Rosario R, Shen Z. Requirement of mouse BCCIP for neural development and progenitor proliferation. PLoS One. 2012;7(1):e30638.CrossRefPubMedPubMedCentral
35.
Leong AS, Haffajee Z. Citraconic anhydride: a new antigen retrieval solution. Pathology. 2010;42(1):77–81.CrossRefPubMed
36.
Namimatsu S, Ghazizadeh M, Sugisaki Y. Reversing the effects of formalin fixation with citraconic anhydride and heat: a universal antigen retrieval method. J Histochem Cytochem. 2005;53(1):3–11.CrossRefPubMed
37.
Neboori HJ, Haffty BG, Wu H, Yang Q, Aly A, Goyal S, Schiff D, Moran MS, Golhar R, Chen C, et al. Low p53 binding protein 1 (53BP1) expression is associated with increased local recurrence in breast cancer patients treated with breast-conserving surgery and radiotherapy. Int J Radiat Oncol Biol Phys. 2012;83(5):e677–83.CrossRefPubMed
38.
Liu X, Cao L, Ni J, Liu N, Zhao X, Wang Y, Zhu L, Wang L, Wang J, Yue Y, et al. Differential BCCIP gene expression in primary human ovarian cancer, renal cell carcinoma and colorectal cancer tissues. Int J Oncol. 2013;43(6):1925–34.CrossRefPubMed
39.
40.
Lin Z, Hu B, Ni W, Mao X, Zhou H, Lv J, Yin B, Shen Z, Wu M, Ding W et al. Expression pattern of BCCIP in hepatocellular carcinoma is correlated with poor prognosis and enhanced cell proliferation. Tumour Biol. 2016;14:6.
41.
Kim MC, Choi JE, Lee SJ, Bae YK. Coexistent loss of the expressions of BRCA1 and p53 predicts poor prognosis in triple-negative breast cancer. Ann Surg Oncol. 2016;23(11):3524–30.CrossRefPubMed
42.
Sun P, Yuan Y, Li A, Li B, Dai X. Cytokeratin expression during mouse embryonic and early postnatal mammary gland development. Histochem Cell Biol. 2010;133(2):213–21.CrossRefPubMed
43.
Rayess H, Wang MB, Srivatsan ES. Cellular senescence and tumor suppressor gene p16. Int J Cancer. 2012;130(8):1715–25.CrossRefPubMed
44.
Romagosa C, Simonetti S, Lopez-Vicente L, Mazo A, Lleonart ME, Castellvi J. Ramon y Cajal S. p16Ink4a overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene. 2011;30(18):2087–97.CrossRefPubMed
45.
Bouwman P, Aly A, Escandell JM, Pieterse M, Bartkova J, van der Gulden H, Hiddingh S, Thanasoula M, Kulkarni A, Yang Q, et al. 53BP1 loss rescues BRCA1 deficiency and is associated with triple-negative and BRCA-mutated breast cancers. Nat Struct Mol Biol. 2010;17(6):688–95.CrossRefPubMedPubMedCentral
46.
Cao L, Xu X, Bunting SF, Liu J, Wang RH, Cao LL, Wu JJ, Peng TN, Chen J, Nussenzweig A, et al. A selective requirement for 53BP1 in the biological response to genomic instability induced by Brca1 deficiency. Mol Cell. 2009;35(4):534–41.CrossRefPubMedPubMedCentral
47.
Bunting SF, Callen E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, et al. 53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks. Cell. 2010;141(2):243–54.CrossRefPubMedPubMedCentral
48.
Bunting SF, Callen E, Kozak ML, Kim JM, Wong N, Lopez-Contreras AJ, Ludwig T, Baer R, Faryabi RB, Malhowski A, et al. BRCA1 functions independently of homologous recombination in DNA interstrand crosslink repair. Mol Cell. 2012;46(2):125–35.CrossRefPubMedPubMedCentral
49.
Li M, Cole F, Patel DS, Misenko SM, Her J, Malhowski A, Alhamza A, Zheng H, Baer R, Ludwig T, et al. 53BP1 ablation rescues genomic instability in mice expressing “RING-less” BRCA1. EMBO Rep. 2016;17(11):1532–41.CrossRefPubMed
50.
Jaspers JE, Kersbergen A, Boon U, Sol W, van Deemter L, Zander SA, Drost R, Wientjens E, Ji J, Aly A, et al. Loss of 53BP1 causes PARP inhibitor resistance in Brca1-mutated mouse mammary tumors. Cancer Discov. 2013;3(1):68–81.CrossRefPubMed
51.
Gupta A, Hunt CR, Chakraborty S, Pandita RK, Yordy J, Ramnarain DB, Horikoshi N, Pandita TK. Role of 53BP1 in the regulation of DNA double-strand break repair pathway choice. Radiat Res. 2014;181(1):1–8.CrossRefPubMed
52.
Panier S, Boulton SJ. Double-strand break repair: 53BP1 comes into focus. Nat Rev Mol Cell Biol. 2014;15(1):7–18.CrossRefPubMed
53.
Coulombe PA, Kopan R, Fuchs E. Expression of keratin K14 in the epidermis and hair follicle: insights into complex programs of differentiation. J Cell Biol. 1989;109(5):2295–312.CrossRefPubMed
54.
Bowman-Colin C, Xia B, Bunting S, Klijn C, Drost R, Bouwman P, Fineman L, Chen X, Culhane AC, Cai H, et al. Palb2 synergizes with Trp53 to suppress mammary tumor formation in a model of inherited breast cancer. Proc Natl Acad Sci U S A. 2013;110(21):8632–7.CrossRefPubMedPubMedCentral
55.
56.
Lam SY, Kasthoori JJ, Mun KS, Rahmat K. Epidermal inclusion cyst of the breast: a rare benign entity. Singap Med J. 2010;51(12):e191–4.
57.
Paliotta A, Sapienza P, D’Ermo G, Cerone G, Pedulla G, Crocetti D, DE Goria A, DE Toma G. Epidermal inclusion cyst of the breast: a literature review. Oncol Lett. 2016;11(1):657–60.PubMed
58.
Suhani, Aggarwal L, Meena K, Ali S, Thomas S. Squamous cell carcinoma arising in epidermal inclusion cyst of breast: a diagnostic dilemma. Breast Dis. 2015;35:25–7.
59.
60.
Mallette FA, Ferbeyre G. The DNA damage signaling pathway connects oncogenic stress to cellular senescence. Cell Cycle. 2007;6(15):1831–6.CrossRefPubMed
61.
Bartkova J, Rezaei N, Liontos M, Karakaidos P, Kletsas D, Issaeva N, Vassiliou L-VF, Kolettas E, Niforou K, Zoumpourlis VC, et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature. 2006;444(7119):633–7.CrossRefPubMed
62.
63.
Schneider BP, Winer EP, Foulkes WD, Garber J, Perou CM, Richardson A, Sledge GW, Carey LA. Triple-negative breast cancer: risk factors to potential targets. Clin Cancer Res. 2008;14(24):8010–8.CrossRefPubMed
Metadata
Title
Roles of BCCIP deficiency in mammary tumorigenesis
Authors
Roberto Droz-Rosario
Huimei Lu
Jingmei Liu
Ning-Ang Liu
Shridar Ganesan
Bing Xia
Bruce G. Haffty
Zhiyuan Shen
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Breast Cancer Research / Issue 1/2017
Electronic ISSN: 1465-542X
DOI
https://doi.org/10.1186/s13058-017-0907-5

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