Synthetic progestins induce growth and metastasis of BT-474 human breast cancer xenografts in nude mice.
OBJECTIVE
Previous studies have shown that sequential exposure to estrogen and progesterone or medroxyprogesterone acetate (MPA) stimulates vascularization and promotes the progression of BT-474 and T47-D human breast cancer cell xenografts in nude mice (Liang et al, Cancer Res 2007, 67:9929). In this follow-up study, the effects of progesterone, MPA, norgestrel (N-EL), and norethindrone (N-ONE) on BT-474 xenograft tumors were compared in the context of several different hormonal environments. N-EL and N-ONE were included in the study because synthetic progestins vary considerably in their biological effects and the effects of these two progestins on the growth of human tumor xenografts are not known.


METHODS
Estradiol-supplemented intact and ovariectomized immunodeficient mice were implanted with BT-474 cells. Progestin pellets were implanted simultaneously with estradiol pellets either 2 days before tumor cell injection (ie, combined) or 5 days after tumor cell injections (ie, sequentially).


RESULTS
Progestins stimulated the growth of BT-474 xenograft tumors independent of exposure timing and protocol, MPA stimulated the growth of BT-474 xenograft tumors in ovariectomized mice, and progestins stimulated vascular endothelial growth factor elaboration and increased tumor vascularity. Progestins also increased lymph node metastasis of BT-474 cells. Therefore, progestins, including N-EL and N-ONE, induce the progression of breast cancer xenografts in nude mice and promote tumor metastasis.


CONCLUSIONS
These observations suggest that women who ingest progestins for hormone therapy or oral contraception could be more at risk for developing breast cancer because of proliferation of existing latent tumor cells. Such risks should be considered in the clinical setting.
Liang
Yayun
Y
Department of Biomedical Sciences, University of Missouri, Columbia, MO 65211, USA.
Benakanakere
Indira
I
Besch-Williford
Cynthia
C
Hyder
Ryyan S
RS
Ellersieck
Mark R
MR
Hyder
Salman M
SM
D000818:Animals; D001943:Breast Neoplasms; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D005260:Female; D020249:Hormone Replacement Therapy / Q000009:adverse effects*; D008207:Lymphatic Metastasis; D051379:Mice; D008819:Mice, Nude; D009640:Norethindrone / Q000494:pharmacology*; D009644:Norgestrel / Q000494:pharmacology*; D045167:Progesterone Congeners / Q000494:pharmacology*; D014183:Transplantation, Heterologous
D045167:Progesterone Congeners; D009644:Norgestrel; D009640:Norethindrone
Int J Cancer. 2004 May 1;109(5):721-7
14999781
Cancer Res. 2005 Nov 1;65(21):9779-88
16266999
Am J Obstet Gynecol. 1997 Jan;176(1 Pt 1):123-8
9024102
Menopause. 2010 Jan-Feb;17(1):178-84
19629015
JAMA. 2003 Jun 25;289(24):3243-53
12824205
Maturitas. 2009 Oct 20;64(2):80-5
19709827
Cancer Res. 1999 Sep 1;59(17):4276-84
10485472
Cancer Res. 1998 Feb 1;58(3):392-5
9458078
Gynecol Endocrinol. 2007 Oct;23 Suppl 1:22-31
17943536
Mol Endocrinol. 2005 Feb;19(2):312-26
15528272
Maturitas. 2002 Jun 25;42(2):93-104
12065168
Int J Gynecol Cancer. 2006;16 Suppl 2:560-3
17010073
Am J Physiol Endocrinol Metab. 2009 Nov;297(5):E1089-96
19690070
Mol Endocrinol. 2007 Jun;21(6):1335-58
17440047
Menopause. 2008 May-Jun;15(3):570-4
18467956
Endocrinology. 2005 Aug;146(8):3632-41
15845615
Breast Cancer Res Treat. 1998 May;49(2):109-17
9696393
Breast Cancer Res Treat. 2004 Feb;83(3):233-44
14758093
Int J Cancer. 2001 May 15;92(4):469-73
11304678
J Clin Pathol. 2001 Jun;54(6):435-40
11376015
Eur J Contracept Reprod Health Care. 2009 Apr;14(2):88-96
19340703
Climacteric. 2002 Sep;5(3):229-35
12419080
J Natl Cancer Inst. 2000 Feb 16;92(4):328-32
10675382
J Steroid Biochem Mol Biol. 2005 Feb;93(2-5):173-82
15860260
Cancer Res. 2007 Oct 15;67(20):9929-36
17942925
Int J Cancer. 2008 Dec 1;123(11):2518-31
18767044
J Cell Physiol. 2001 Apr;187(1):81-9
11241352
Maturitas. 2003 Dec 10;46 Suppl 1:S31-7
14670643
Biochem Biophys Res Commun. 2000 Nov 2;277(3):650-4
11062008
Cancer. 2004 Oct 1;101(7):1490-500
15378477
BMC Cancer. 2008 Jun 09;8:166
18541028