Top

Breast Cancer Research and Treatment

Published in:

01-07-2017 | Preclinical study

Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro

Authors: Lynn N. Thomas, Emily R. Chedrawe, Penelope J. Barnes, Catherine K. L. Too

Published in: Breast Cancer Research and Treatment | Issue 1/2017

Abstract

Purpose

Carboxypeptidase-D (CPD) cleaves C-terminal arginine (Arg) to produce nitric oxide (NO). Upregulation of CPD and NO by 17β-estradiol, prolactin (PRL), and androgen increases survival of human breast cancer (BCa) cells in vitro. To demonstrate similar events in vivo, CPD, nitrotyrosine (NT, hallmark of NO action), androgen receptor (AR), prolactin receptor (PRLR), and phospho-Stat5a (for activated PRLR) levels were evaluated in benign and malignant human breast tissues, and correlated with cell proliferation (Ki67) and BCa progression (Cullin-3) biomarkers.

Methods

Paraffin-embedded breast tissues were analyzed by immunohistochemistry (IHC). BCa progression markers in human MCF-7 and T47D BCa cell lines treated with NO donor SIN-1 or PRL, ±CPD inhibitors were analyzed by RT-qPCR and immunoblotting.

Results

IHC showed progressive increases in CPD, NT, Ki67, and Cullin-3 from low levels in benign tissues to high levels in ductal carcinoma in situ, low-grade, high-grade, and triple-negative BCa. CPD and NT staining were closely associated, implicating CPD in NO production. Phospho-Stat5a increased significantly from benign to high-grade BCa and was mostly nuclear. AR and PRLR were abundant in benign breast and BCa, including triple-negative tumors. SIN-1 and PRL increased VEGF-C and Runx2, but not Cullin-3, in BCa cell lines. PRL induction of VEGF-C and Runx2 was inhibited partly by CPD inhibitors, implicating NO, produced by PRL-regulated CPD, in BCa progression.

Conclusions

The CPD-Arg-NO pathway contributes to BCa progression in vitro and in vivo. PRL/androgen activation of the pathway support combined AR and PRLR blockade as an additional therapy for BCa.

Guiu S, Michiels S, Andre F, Cortes J, Denkert C, Di Leo A, Hennessy BT, Sorlie T, Sotiriou C, Turner N, Van de Vijver M, Viale G, Loi S, Reis-Filho JS (2012) Molecular subclasses of breast cancer: how do we define them? The IMPAKT 2012 working group statement. Ann Oncol 23(12):2997–3006. doi:10.1093/annonc/mds586 CrossRefPubMed

Prat A, Perou CM (2011) Deconstructing the molecular portraits of breast cancer. Mol Oncol 5(1):5–23. doi:10.1016/j.molonc.2010.11.003 CrossRefPubMed

Peppercorn J, Perou CM, Carey LA (2008) Molecular subtypes in breast cancer evaluation and management: divide and conquer. Cancer Invest 26(1):1–10. doi:10.1080/07357900701784238 CrossRefPubMed

McGuire WL, Osborne CK, Clark GM, Knight WA (1982) Steroid hormone receptors and carcinoma of the breast. Am J Physiol 243(2):E99–E102PubMed

Dean-Colomb W, Esteva FJ (2008) Her2-positive breast cancer: herceptin and beyond. Eur J Cancer 44(18):2806–2812. doi:10.1016/j.ejca.2008.09.013 CrossRefPubMed

Elias AD (2010) Triple-negative breast cancer: a short review. Am J Clin Oncol 33(6):637–645. doi:10.1097/COC.0b013e3181b8afcf CrossRefPubMed

Foulkes WD, Smith IE, Reis-Filho JS (2010) Triple-negative breast cancer. N Engl J Med 363(20):1938–1948. doi:10.1056/NEJMra1001389 CrossRefPubMed

Birrell SN, Hall RE, Tilley WD (1998) Role of the androgen receptor in human breast cancer. J Mammary Gland Biol Neoplasia 3(1):95–103CrossRefPubMed

Park S, Koo J, Park HS, Kim JH, Choi SY, Lee JH, Park BW, Lee KS (2010) Expression of androgen receptors in primary breast cancer. Ann Oncol 21(3):488–492. doi:10.1093/annonc/mdp510 CrossRefPubMed

10.

Reynolds C, Montone KT, Powell CM, Tomaszewski JE, Clevenger CV (1997) Expression of prolactin and its receptor in human breast carcinoma. Endocrinology 138(12):5555–5560. doi:10.1210/endo.138.12.5605 CrossRefPubMed

11.

Howlader N, Altekruse SF, Li CI, Chen VW, Clarke CA, Ries LA, Cronin KA (2014) US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status. J Natl Cancer Inst. doi:10.1093/jnci/dju055 PubMedPubMedCentral

12.

Rakha EA, Pinder SE, Bartlett JM, Ibrahim M, Starczynski J, Carder PJ, Provenzano E, Hanby A, Hales S, Lee AH, Ellis IO, National Coordinating Committee for Breast P (2015) Updated UK recommendations for HER2 assessment in breast cancer. J Clin Pathol 68(2):93–99. doi:10.1136/jclinpath-2014-202571 CrossRefPubMed

13.

Krishnamurti U, Silverman JF (2014) HER2 in breast cancer: a review and update. Adv Anat Pathol 21(2):100–107. doi:10.1097/PAP.0000000000000015 CrossRefPubMed

14.

Purdie CA, Quinlan P, Jordan LB, Ashfield A, Ogston S, Dewar JA, Thompson AM (2014) Progesterone receptor expression is an independent prognostic variable in early breast cancer: a population-based study. Br J Cancer 110(3):565–572. doi:10.1038/bjc.2013.756 CrossRefPubMed

15.

Muir D, Kanthan R, Kanthan SC (2003) Male versus female breast cancers. A population-based comparative immunohistochemical analysis. Arch Pathol Lab Med 127(1):36–41. doi:10.1043/0003-9985(2003)127<36:MVFB>2.0.CO;2 PubMed

16.

Birrell SN, Bentel JM, Hickey TE, Ricciardelli C, Weger MA, Horsfall DJ, Tilley WD (1995) Androgens induce divergent proliferative responses in human breast cancer cell lines. J Steroid Biochem Mol Biol 52(5):459–467CrossRefPubMed

17.

Somboonporn W, Davis SR, National H, Medical Research C (2004) Testosterone effects on the breast: implications for testosterone therapy for women. Endocr Rev 25(3):374–388. doi:10.1210/er.2003-0016 CrossRefPubMed

18.

Dorgan JF, Longcope C, Stephenson HE Jr, Falk RT, Miller R, Franz C, Kahle L, Campbell WS, Tangrea JA, Schatzkin A (1996) Relation of prediagnostic serum estrogen and androgen levels to breast cancer risk. Cancer Epidemiol Biomarkers Prev 5(7):533–539PubMed

19.

Wysowski DK, Comstock GW, Helsing KJ, Lau HL (1987) Sex hormone levels in serum in relation to the development of breast cancer. Am J Epidemiol 125(5):791–799CrossRefPubMed

20.

Hankinson SE, Willett WC, Manson JE, Colditz GA, Hunter DJ, Spiegelman D, Barbieri RL, Speizer FE (1998) Plasma sex steroid hormone levels and risk of breast cancer in postmenopausal women. J Natl Cancer Inst 90(17):1292–1299CrossRefPubMed

21.

Cochrane DR, Bernales S, Jacobsen BM, Cittelly DM, Howe EN, D’Amato NC, Spoelstra NS, Edgerton SM, Jean A, Guerrero J, Gomez F, Medicherla S, Alfaro IE, McCullagh E, Jedlicka P, Torkko KC, Thor AD, Elias AD, Protter AA, Richer JK (2014) Role of the androgen receptor in breast cancer and preclinical analysis of enzalutamide. Breast Cancer Res 16(1):R7. doi:10.1186/bcr3599 CrossRefPubMedPubMedCentral

22.

Kelly PA, Djiane J, Postel-Vinay MC, Edery M (1991) The prolactin/growth hormone receptor family. Endocr Rev 12(3):235–251CrossRefPubMed

23.

Ginsburg E, Vonderhaar BK (1995) Prolactin synthesis and secretion by human breast cancer cells. Cancer Res 55(12):2591–2595PubMed

24.

Clevenger CV, Plank TL (1997) Prolactin as an autocrine/paracrine factor in breast tissue. J Mammary Gland Biol Neoplasia 2(1):59–68CrossRefPubMed

25.

Holtkamp W, Nagel GA, Wander HE, Rauschecker HF, von Heyden D (1984) Hyperprolactinemia is an indicator of progressive disease and poor prognosis in advanced breast cancer. Int J Cancer 34(3):323–328CrossRefPubMed

26.

Hankinson SE, Willett WC, Michaud DS, Manson JE, Colditz GA, Longcope C, Rosner B, Speizer FE (1999) Plasma prolactin levels and subsequent risk of breast cancer in postmenopausal women. J Natl Cancer Inst 91(7):629–634CrossRefPubMed

27.

Hachim IY, Hachim MY, Lopez VM, Lebrun JJ, Ali S (2016) Prolactin receptor expression is an independent favorable prognostic marker in human breast cancer. Appl Immunohistochem Mol Morphol 24(4):238–245. doi:10.1097/PAI.0000000000000178 CrossRefPubMed

28.

Hachim IY, Shams A, Lebrun JJ, Ali S (2016) A favorable role of prolactin in human breast cancer reveals novel pathway-based gene signatures indicative of tumor differentiation and favorable patient outcome. Hum Pathol 53:142–152. doi:10.1016/j.humpath.2016.02.010 CrossRefPubMed

29.

Lopez-Ozuna VM, Hachim IY, Hachim MY, Lebrun JJ, Ali S (2016) Prolactin pro-differentiation pathway in triple negative breast cancer: impact on prognosis and potential therapy. Sci Rep 6:30934. doi:10.1038/srep30934 CrossRefPubMedPubMedCentral

30.

Migliaccio A, Di Domenico M, Castoria G, de Falco A, Bontempo P, Nola E, Auricchio F (1996) Tyrosine kinase/p21ras/MAP-kinase pathway activation by estradiol-receptor complex in MCF-7 cells. Embo J 15(6):1292–1300PubMedPubMedCentral

31.

Migliaccio A, Varricchio L, De Falco A, Castoria G, Arra C, Yamaguchi H, Ciociola A, Lombardi M, Di Stasio R, Barbieri A, Baldi A, Barone MV, Appella E, Auricchio F (2007) Inhibition of the SH3 domain-mediated binding of Src to the androgen receptor and its effect on tumor growth. Oncogene 26(46):6619–6629. doi:10.1038/sj.onc.1210487 CrossRefPubMed

32.

Gutzman JH, Rugowski DE, Schroeder MD, Watters JJ, Schuler LA (2004) Multiple kinase cascades mediate prolactin signals to activating protein-1 in breast cancer cells. Mol Endocrinol 18(12):3064–3075CrossRefPubMedPubMedCentral

33.

Skidgel RA, Erdos EG (1998) Cellular carboxypeptidases. Immunol Rev 161:129–141CrossRefPubMed

34.

Song L, Fricker LD (1995) Purification and characterization of carboxypeptidase D, a novel carboxypeptidase E-like enzyme, from bovine pituitary. J Biol Chem 270(42):25007–25013CrossRefPubMed

35.

Song L, Fricker LD (1996) Tissue distribution and characterization of soluble and membrane-bound forms of metallocarboxypeptidase D. J Biol Chem 271(46):28884–28889CrossRefPubMed

36.

Tan F, Rehli M, Krause SW, Skidgel RA (1997) Sequence of human carboxypeptidase D reveals it to be a member of the regulatory carboxypeptidase family with three tandem active site domains. Biochem J 327(Pt 1):81–87CrossRefPubMedPubMedCentral

37.

Novikova EG, Eng FJ, Yan L, Qian Y, Fricker LD (1999) Characterization of the enzymatic properties of the first and second domains of metallocarboxypeptidase D. J Biol Chem 274(41):28887–28892CrossRefPubMed

38.

O’Malley PG, Sangster SM, Abdelmagid SA, Bearne SL, Too CKL (2005) Characterization of a novel, cytokine-inducible carboxypeptidase D isoform in haematopoietic tumour cells. Biochem J 390(Pt 3):665–673. doi:10.1042/BJ20050025 CrossRefPubMedPubMedCentral

39.

Abdelmagid SA, Too CKL (2008) Prolactin and estrogen upregulate carboxypeptidase-D to promote nitric oxide production and survival of MCF-7 breast cancer cells. Endocinology 149(10):4821–4828. doi:10.1210/en.2008-0145 CrossRef

40.

Abdelmagid SA, Rickard JA, McDonald WJ, Thomas LN, Too CKL (2011) CAT-1-mediated arginine uptake and regulation of nitric oxide synthases for the survival of human breast cancer cell lines. J Cell Biochem 112(4):1084–1092. doi:10.1002/jcb.23022 CrossRefPubMed

41.

Koirala S, Thomas LN, Too CKL (2014) Prolactin/Stat5 and androgen R1881 coactivate carboxypeptidase-D gene in breast cancer cells. Mol Endocrinol 28(3):331–343. doi:10.1210/me.2013-1202 CrossRefPubMedPubMedCentral

42.

Thomas LN, Morehouse TJ, Too CKL (2012) Testosterone and prolactin increase carboxypeptidase-D and nitric oxide levels to promote survival of prostate cancer cells. Prostate 72(4):450–460. doi:10.1002/pros.21446 CrossRefPubMed

43.

Thomas LN, Merrimen J, Bell DG, Rendon R, Goffin V, Too CKL (2014) Carboxypeptidase-D is elevated in prostate cancer and its anti-apoptotic activity is abolished by combined androgen and prolactin receptor targeting. Prostate 74(7):732–742. doi:10.1002/pros.22793 CrossRefPubMed

44.

Thomas LN, Merrimen J, Bell DG, Rendon R, Too CKL (2015) Prolactin- and testosterone-induced carboxypeptidase-D correlates with increased nitrotyrosines and Ki67 in prostate cancer. Prostate 75:1726–1736. doi:10.1002/pros.23054 CrossRefPubMed

45.

Jin T, Fu J, Feng XJ, Wang SM, Huang X, Zhu MH, Zhang SH (2013) SiRNA-targeted carboxypeptidase D inhibits hepatocellular carcinoma growth. Cell Biol Int 37:929–939. doi:10.1002/cbin.10113 CrossRefPubMed

46.

Bouzubar N, Walker KJ, Griffiths K, Ellis IO, Elston CW, Robertson JF, Blamey RW, Nicholson RI (1989) Ki67 immunostaining in primary breast cancer: pathological and clinical associations. Br J Cancer 59(6):943–947CrossRefPubMedPubMedCentral

47.

Pathmanathan N, Balleine RL (2013) Ki67 and proliferation in breast cancer. J Clin Pathol 66(6):512–516. doi:10.1136/jclinpath-2012-201085 CrossRefPubMed

48.

Mikalsen LT, Dhakal HP, Bruland OS, Nesland JM, Olsen DR (2011) Quantification of angiogenesis in breast cancer by automated vessel identification in CD34 immunohistochemical sections. Anticancer Res 31(12):4053–4060PubMed

49.

Haagenson KK, Tait L, Wang J, Shekhar MP, Polin L, Chen W, Wu GS (2012) Cullin-3 protein expression levels correlate with breast cancer progression. Cancer Biol Ther 13(11):1042–1046. doi:10.4161/cbt.21046 CrossRefPubMedPubMedCentral

50.

Huo X, Li S, Shi T, Suo A, Ruan Z, Guo H, Yao Y (2015) Cullin3 promotes breast cancer cells metastasis and epithelial-mesenchymal transition by targeting BRMS1 for degradation. Oncotarget 6(39):41959–41975. doi:10.18632/oncotarget.5999 PubMedPubMedCentral

51.

Too CKL, Vickaryous N, Boudreau RT, Sangster SM (2001) Identification and nuclear localization of a novel prolactin and cytokine-responsive carboxypeptidase D. Endocrinology 142(3):1357–1367. doi:10.1210/endo.142.3.8041 CrossRefPubMed

52.

Goffin V, Bogorad RL, Touraine P (2010) Identification of gain-of-function variants of the human prolactin receptor. Methods Enzymol 484:329–355. doi:10.1016/B978-0-12-381298-8.00017-4 CrossRefPubMed

53.

Chauhan H, Abraham A, Phillips JR, Pringle JH, Walker RA, Jones JL (2003) There is more than one kind of myofibroblast: analysis of CD34 expression in benign, in situ, and invasive breast lesions. J Clin Pathol 56(4):271–276CrossRefPubMedPubMedCentral

54.

Fiorillo AA, Medler TR, Feeney YB, Liu Y, Tommerdahl KL, Clevenger CV (2011) HMGN2 inducibly binds a novel transactivation domain in nuclear PRLr to coordinate Stat5a-mediated transcription. Mol Endocrinol 25(9):1550–1564. doi:10.1210/me.2011-0106 CrossRefPubMedPubMedCentral

55.

Nevalainen MT, Xie J, Torhorst J, Bubendorf L, Haas P, Kononen J, Sauter G, Rui H (2004) Signal transducer and activator of transcription-5 activation and breast cancer prognosis. J Clin Oncol 22(11):2053–2060. doi:10.1200/JCO.2004.11.046 CrossRefPubMed

56.

Peck AR, Witkiewicz AK, Liu C, Stringer GA, Klimowicz AC, Pequignot E, Freydin B, Tran TH, Yang N, Rosenberg AL, Hooke JA, Kovatich AJ, Nevalainen MT, Shriver CD, Hyslop T, Sauter G, Rimm DL, Magliocco AM, Rui H (2011) Loss of nuclear localized and tyrosine phosphorylated Stat5 in breast cancer predicts poor clinical outcome and increased risk of antiestrogen therapy failure. J Clin Oncol 29(18):2448–2458. doi:10.1200/JCO.2010.30.3552 CrossRefPubMedPubMedCentral

57.

Jadeski LC, Lala PK (1999) Nitric oxide synthase inhibition by N(G)-nitro-L-arginine methyl ester inhibits tumor-induced angiogenesis in mammary tumors. Am J Pathol 155(4):1381–1390CrossRefPubMedPubMedCentral

58.

Nakamura Y, Yasuoka H, Tsujimoto M, Yoshidome K, Nakahara M, Nakao K, Nakamura M, Kakudo K (2006) Nitric oxide in breast cancer: induction of vascular endothelial growth factor-C and correlation with metastasis and poor prognosis. Clin Cancer Res 12(4):1201–1207. doi:10.1158/1078-0432.CCR-05-1269 CrossRefPubMed

59.

Tandon M, Chen Z, Pratap J (2014) Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells. Breast Cancer Res 16(1):R16. doi:10.1186/bcr3611 CrossRefPubMedPubMedCentral

60.

Furth PA, Nakles RE, Millman S, Diaz-Cruz ES, Cabrera MC (2011) Signal transducer and activator of transcription 5 as a key signaling pathway in normal mammary gland developmental biology and breast cancer. Breast Cancer Res 13(5):220. doi:10.1186/bcr2921 CrossRefPubMedPubMedCentral

61.

Cotarla I, Ren S, Zhang Y, Gehan E, Singh B, Furth PA (2004) Stat5a is tyrosine phosphorylated and nuclear localized in a high proportion of human breast cancers. Int J Cancer 108(5):665–671. doi:10.1002/ijc.11619 CrossRefPubMed

62.

Wagner KU, Rui H (2008) Jak2/Stat5 signaling in mammogenesis, breast cancer initiation and progression. J Mammary Gland Biol Neoplasia 13(1):93–103. doi:10.1007/s10911-008-9062-z CrossRefPubMed

63.

Barash I (2012) Stat5 in breast cancer: potential oncogenic activity coincides with positive prognosis for the disease. Carcinogenesis 33(12):2320–2325. doi:10.1093/carcin/bgs362 CrossRefPubMed

64.

Beckman JS, Koppenol WH (1996) Nitric oxide, superoxide, and peroxynitrite: the good, the bad, and ugly. Am J Physiol 271(5 Pt 1):C1424–C1437PubMed

65.

Thomsen LL, Miles DW (1998) Role of nitric oxide in tumour progression: lessons from human tumours. Cancer Metastasis Rev 17(1):107–118CrossRefPubMed

66.

Orucevic A, Bechberger J, Green AM, Shapiro RA, Billiar TR, Lala PK (1999) Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Int J Cancer 81(6):889–896CrossRefPubMed

67.

Fukumura D, Kashiwagi S, Jain RK (2006) The role of nitric oxide in tumour progression. Nat Rev Cancer 6(7):521–534. doi:10.1038/nrc1910 CrossRefPubMed

68.

Hirst D, Robson T (2010) Nitric oxide in cancer therapeutics: interaction with cytotoxic chemotherapy. Curr Pharm Des 16(4):411–420CrossRefPubMed

69.

Lehmann BD, Bauer JA, Chen X, Sanders ME, Chakravarthy AB, Shyr Y, Pietenpol JA (2011) Identification of human triple-negative breast cancer subtypes and preclinical models for selection of targeted therapies. J Clin Invest 121(7):2750–2767. doi:10.1172/JCI45014 CrossRefPubMedPubMedCentral

70.

Rampurwala M, Wisinski KB, O’Regan R (2016) Role of the androgen receptor in triple-negative breast cancer. Clin Adv Hematol Oncol 14(3):186–193PubMedPubMedCentral

71.

Gucalp A, Tolaney S, Isakoff SJ, Ingle JN, Liu MC, Carey LA, Blackwell K, Rugo H, Nabell L, Forero A, Stearns V, Doane AS, Danso M, Moynahan ME, Momen LF, Gonzalez JM, Akhtar A, Giri DD, Patil S, Feigin KN, Hudis CA, Traina TA, Translational Breast Cancer Research C (2013) Phase II trial of bicalutamide in patients with androgen receptor-positive, estrogen receptor-negative metastatic breast cancer. Clin Cancer Res 19(19):5505–5512. doi:10.1158/1078-0432.CCR-12-3327 CrossRefPubMedPubMedCentral

72.

Traina T, Miller K, Yardley D, O’Shaughnessy J, Cortes J, Awada A, Kelly C, Trudeau M, Schmid P, Gianni L, García-Estevez L, Nanda R, Ademuyiwa F, Chan S, Steinberg J, Blaney M, Tudor I, Uppal H, Peterson A, Hudis C (2015) Results from a phase 2 study of enzalutamide (ENZA), an androgen receptor (AR) inhibitor, in advanced AR+ triple-negative breast cancer (TNBC). J Clin Oncol 33(suppl; abstr):1003

73.

Proverbs-Singh T, Feldman JL, Morris MJ, Autio KA, Traina TA (2015) Targeting the androgen receptor in prostate and breast cancer: several new agents in development. Endocr Relat Cancer 22(3):R87–R106. doi:10.1530/ERC-14-0543 CrossRefPubMedPubMedCentral

74.

Gucalp A, Traina TA (2016) Targeting the androgen receptor in triple-negative breast cancer. Curr Probl Cancer 40(2–4):141–150. doi:10.1016/j.currproblcancer.2016.09.004 CrossRefPubMed

75.

Goffin V, Bernichtein S, Touraine P, Kelly PA (2005) Development and potential clinical uses of human prolactin receptor antagonists. Endocr Rev 26(3):400–422. doi:10.1210/er.2004-0016 CrossRefPubMed

76.

Bernichtein S, Kayser C, Dillner K, Moulin S, Kopchick JJ, Martial JA, Norstedt G, Isaksson O, Kelly PA, Goffin V (2003) Development of pure prolactin receptor antagonists. J Biol Chem 278(38):35988–35999. doi:10.1074/jbc.M305687200 CrossRefPubMed

77.

Bernichtein S, Touraine P, Goffin V (2010) New concepts in prolactin biology. J Endocrinol. doi:10.1677/JOE-10-0069 PubMed

78.

Goffin V, Touraine P (2015) The prolactin receptor as a therapeutic target in human diseases: browsing new potential indications. Expert Opin Ther Targets 19(9):1229–1244. doi:10.1517/14728222.2015.1053209 CrossRefPubMed

79.

Damiano JS, Rendahl KG, Karim C, Embry MG, Ghoddusi M, Holash J, Fanidi A, Abrams TJ, Abraham JA (2013) Neutralization of prolactin receptor function by monoclonal antibody LFA102, a novel potential therapeutic for the treatment of breast cancer. Mol Cancer Ther 12(3):295–305. doi:10.1158/1535-7163.MCT-12-0886 CrossRefPubMed

80.

Damiano JS, Wasserman E (2013) Molecular pathways: blockade of the PRLR signaling pathway as a novel antihormonal approach for the treatment of breast and prostate cancer. Clin Cancer Res 19(7):1644–1650. doi:10.1158/1078-0432.CCR-12-0138 CrossRefPubMed

81.

Agarwal N, Machiels JP, Suarez C, Lewis N, Higgins M, Wisinski K, Awada A, Maur M, Stein M, Hwang A, Mosher R, Wasserman E, Wu G, Zhang H, Zieba R, Elmeliegy M (2016) Phase I study of the prolactin receptor antagonist LFA102 in metastatic breast and castration-resistant prostate cancer. Oncologist 21(5):535–536. doi:10.1634/theoncologist.2015-0502 CrossRefPubMedPubMedCentral

82.

O’Sullivan CC, Bates SE (2016) Targeting Prolactin receptor (PRLR) signaling in PRLR-positive breast and prostate cancer. Oncologist 21(5):523–526. doi:10.1634/theoncologist.2016-0108 CrossRefPubMedPubMedCentral

Title: Prolactin/androgen-inducible carboxypeptidase-D increases with nitrotyrosine and Ki67 for breast cancer progression in vivo, and upregulates progression markers VEGF-C and Runx2 in vitro
Authors: Lynn N. Thomas
Emily R. Chedrawe
Penelope J. Barnes
Catherine K. L. Too
Publication date: 01-07-2017
Publisher: Springer US
Published in: Breast Cancer Research and Treatment / Issue 1/2017
Print ISSN: 0167-6806
Electronic ISSN: 1573-7217
DOI: https://doi.org/10.1007/s10549-017-4223-7

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

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 1/2017

The relationship between statins and breast cancer prognosis varies by statin type and exposure time: a meta-analysis

Changes in arm tissue composition with slowly progressive weight-lifting among women with breast cancer-related lymphedema

Which women decide to take tamoxifen?

Assessment of the prognostic and discriminating value of the novel bioscore system for breast cancer; a SEER database analysis

Differential impact of hormone receptor status on survival and recurrence for HER2 receptor-positive breast cancers treated with Trastuzumab

Racial disparity in vitamin D status may explain racial disparity in survival from estrogen and progesterone receptor-positive breast cancer

Keynote webinar | Spotlight on antibody–drug conjugates in cancer