title: Aromatase expression increases the survival and malignancy of estrogen receptor positive breast cancer cells.
abstract: In postmenopausal women, local estrogen produced by adipose stromal cells in the breast is believed to support estrogen receptor alpha (ERα) positive breast cancer cell survival and growth. This raises the question of how the ERα positive metastatic breast cancer cells survive after they enter blood and lymph circulation, where estrogen level is very low in postmenopausal women. In this study, we show that the aromatase expression increased when ERα positive breast cancer cells were cultured in suspension. Furthermore, treatment with the aromatase substrate, testosterone, inhibited suspension culture-induced apoptosis whereas an aromatase inhibitor attenuated the effect of testosterone suggesting that suspended circulating ERα positive breast cancer cells may up-regulate intracrine estrogen activity for survival. Consistent with this notion, a moderate level of ectopic aromatase expression rendered a non-tumorigenic ERα positive breast cancer cell line not only tumorigenic but also metastatic in female nude mice without exogenous estrogen supplementation. The increased malignant phenotype was confirmed to be due to aromatase expression as the growth of orthotopic tumors regressed with systemic administration of an aromatase inhibitor. Thus, our study provides experimental evidence that aromatase plays an important role in the survival of metastatic ERα breast cancer cells by suppressing anoikis.
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America.
authors.forename: Keya De
authors.initials: KD
authors.lastname: Mukhopadhyay
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America; Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America.
authors.forename: Abhik
authors.initials: A
authors.lastname: Bandyopadhyay
authors.affiliation: Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, United States of America.
authors.forename: Nameer B
authors.initials: NB
authors.lastname: Kirma
authors.affiliation: Department of Obstetrics and Gynecology, University of Texas Health Science Center, San Antonio, United States of America; Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, United States of America.
authors.forename: Rajeshwar R
authors.initials: RR
authors.lastname: Tekmal
authors.affiliation: Department of Breast Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.
authors.forename: Shui
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, United States of America; Cancer Therapy and Research Center, University of Texas Health Science Center, San Antonio, United States of America.
authors.forename: Lu-Zhe
authors.initials: LZ
authors.lastname: Sun
mesh_terms: D000818:Animals; D023102:Anoikis / Q000235:genetics; D001141:Aromatase / Q000235:genetics* / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000494:pharmacology; D001859:Bone Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000556:secondary; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D044584:Carcinoma, Ductal / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics* / Q000556:secondary; D045744:Cell Line, Tumor; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism; D004967:Estrogens / Q000096:biosynthesis; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000077289:Letrozole; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009570:Nitriles / Q000494:pharmacology; D015398:Signal Transduction; D013739:Testosterone / Q000378:metabolism / Q000494:pharmacology; D014230:Triazoles / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D047072:Aromatase Inhibitors; D047628:Estrogen Receptor alpha; D004967:Estrogens; D009570:Nitriles; D014230:Triazoles; D013739:Testosterone; D000077289:Letrozole; D001141:Aromatase
references.citation: Breast Cancer Res Treat. 2006 Sep;99(2):155-62
references.pmid: 16541304
references.citation: J Steroid Biochem Mol Biol. 2006 Dec;102(1-5):89-96
references.pmid: 17113977
references.citation: Am J Physiol Endocrinol Metab. 2007 Jan;292(1):E246-52
references.pmid: 16940470
references.citation: Rev Endocr Metab Disord. 2007 Sep;8(3):215-28
references.pmid: 17486453
references.citation: Expert Rev Anticancer Ther. 2008 Jan;8(1):1-4
references.pmid: 18095876
references.citation: Mol Endocrinol. 2009 May;23(5):662-70
references.pmid: 19221050
references.citation: CA Cancer J Clin. 2012 Jan-Feb;62(1):10-29
references.pmid: 22237781
references.citation: Annu Rev Physiol. 2002;64:93-127
references.pmid: 11826265
references.citation: Recent Prog Horm Res. 2002;57:317-38
references.pmid: 12017550
references.citation: Cancer Biol Ther. 2003 Jan-Feb;2(1):14-21
references.pmid: 12673112
references.citation: N Engl J Med. 2003 Jun 5;348(23):2339-47
references.pmid: 12788999
references.citation: Cancer Res. 2003 Jul 1;63(13):3546-55
references.pmid: 12839940
references.citation: Obes Rev. 2004 Aug;5(3):153-65
references.pmid: 15245384
references.citation: Exp Eye Res. 1987 Jan;44(1):17-28
references.pmid: 3104073
references.citation: Mol Endocrinol. 1989 Aug;3(8):1215-22
references.pmid: 2674694
references.citation: Bone. 1991;12 Suppl 1:S9-10
references.pmid: 1954049
references.citation: Endocr Rev. 1994 Jun;15(3):342-55
references.pmid: 8076586
references.citation: Cancer Res. 1994 Oct 1;54(19):5092-5
references.pmid: 7923123
references.citation: Cancer Res. 1995 Jun 15;55(12):2487-9
references.pmid: 7780952
references.citation: Steroids. 1998 May-Jun;63(5-6):322-8
references.pmid: 9618795
references.citation: Breast Cancer Res Treat. 1999 Feb;53(3):217-27
references.pmid: 10369068
references.citation: Breast Cancer Res. 2004;6(6):246-54
references.pmid: 15535854
references.citation: Clin Exp Metastasis. 2004;21(4):313-9
references.pmid: 15554387
references.citation: Oncogene. 2005 Mar 24;24(13):2236-46
references.pmid: 15688015
references.citation: Cancer Res. 2005 Dec 1;65(23):11164-73
references.pmid: 16322267
references.citation: Cancer Res. 2006 Jul 1;66(13):6714-21
references.pmid: 16818646