Amphiregulin mediates estrogen, progesterone, and EGFR signaling in the normal rat mammary gland and in hormone-dependent rat mammary cancers.
Both estrogen (E) and progesterone (P) are implicated in the etiology of human breast cancer. Defining their mechanisms of action, particularly in vivo, is relevant to the prevention and therapy of breast cancer. We investigated the molecular and cellular mechanisms of E and/or P-induced in vivo proliferation, in the normal rat mammary gland and in hormone-dependent rat mammary cancers which share many characteristics with the normal human breast and hormone-dependent breast cancers. We show that E+P treatment induced significantly greater proliferation in both the normal gland and mammary cancers compared to E alone. In both the normal gland and tumors, E+P-induced proliferation was mediated through the increased production of amphiregulin (Areg), an epidermal growth factor receptor (EGFR) ligand, and the activation of intracellular signaling pathways (Erk, Akt, JNK) downstream of EGFR that regulate proliferation. In vitro experiments using rat primary mammary organoids or T47D breast cancer cells confirmed that Areg and the synthetic progestin, R5020, synergize to promote cell proliferation through EGFR signaling. Iressa, an EGFR inhibitor, effectively blocked this proliferation. These results indicate that mediators of cross talk between E, P, and EGFR pathways may be considered as relevant molecular targets for the therapy of hormone-dependent breast cancers, especially in premenopausal women.
Department of Physiology, Breast Cancer and the Environment Research Center, Michigan State University, 2201 Biomedical & Physical Sciences Bldg, East Lansing, MI, USA.
Anastasia
A
Kariagina
Jianwei
J
Xie
Jeffrey R
JR
Leipprandt
Sandra Z
SZ
Haslam
D066258:Amphiregulin; D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D066255:EGF Family of Proteins; D066246:ErbB Receptors / Q000378:metabolism*; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation / Q000502:physiology; D006023:Glycoproteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism*; D009376:Neoplasms, Hormone-Dependent / Q000378:metabolism; D011374:Progesterone / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
C587848:AREG protein, human; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D004967:Estrogens; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D011374:Progesterone; D066246:ErbB Receptors
Mol Cell Biol. 2004 Dec;24(24):10542-57
15572662
J Biol Chem. 2008 Jan 11;283(2):739-50
17942395
Int Arch Allergy Immunol. 2009;149 Suppl 1:39-44
19494503
J Biol Chem. 1998 Nov 20;273(47):31308-16
9813039
Br J Cancer. 2006 Jun 5;94(11):1604-9
16685276
Anal Biochem. 2005 Mar 1;338(1):136-42
15707944
Mol Endocrinol. 1999 Oct;13(10):1657-71
10517668
Mol Cancer Ther. 2008 Apr;7(4):972-9
18375820
J Steroid Biochem Mol Biol. 2005 Jul;96(2):95-108
15908197
Breast Cancer Res. 2002;4(5):187-90
12223122
J Mammary Gland Biol Neoplasia. 2008 Jun;13(2):181-94
18470483
Genes Dev. 2000 Mar 15;14(6):650-4
10733525
Endocr Relat Cancer. 2006 Jun;13(2):617-28
16728587
Endocrinology. 1994 Jan;134(1):84-90
8275973
Menopause. 2006 Jan-Feb;13(1):72-9
16607101
Pathobiology. 2006;73(5):213-23
17314492
Endocrinology. 2007 Jun;148(6):2723-36
17332059
Mol Cell Biol. 2006 Feb;26(3):1002-13
16428453
Int J Biol Markers. 2008 Jan-Mar;23(1):1-9
18409144
Horm Res. 2000;54(1):32-7
11182633
J Steroid Biochem Mol Biol. 2009 Feb;113(3-5):163-70
19103290
J Mammary Gland Biol Neoplasia. 2002 Jan;7(1):3-15
12160084
In Vivo. 2003 Jul-Aug;17(4):349-57
12929590
JAMA. 2010 Oct 20;304(15):1684-92
20959578
Steroids. 2007 Feb;72(2):188-201
17173941
Breast Cancer Res Treat. 2002 Mar;72(2):163-72
12038707
Mol Endocrinol. 2008 Apr;22(4):823-37
18202149
Endocrinology. 2004 Jan;145(1):104-12
14512435
Mol Endocrinol. 2006 Nov;20(11):2656-70
16762974
Breast Cancer Res Treat. 1996;39(1):7-20
8738602
J Biol Chem. 2002 Feb 15;277(7):5209-18
11717311
Am J Physiol Endocrinol Metab. 2005 Nov;289(5):E857-63
15985451
J Clin Endocrinol Metab. 1999 Dec;84(12):4559-65
10599719
Mol Endocrinol. 1999 Jun;13(6):829-36
10379882
Proc Natl Acad Sci U S A. 2000 Feb 1;97(3):1032-7
10655479
Mol Endocrinol. 2007 Feb;21(2):359-75
17138644
Dev Biol. 2006 Jul 15;295(2):589-603
16678816
Nature. 2010 Nov 4;468(7320):98-102
20881962
Mol Cell Biol. 2001 Sep;21(18):6122-31
11509655
J Mammary Gland Biol Neoplasia. 2003 Apr;8(2):215-23
14635796
Endocrinology. 2008 May;149(5):2098-107
18218689
Endocrinology. 2005 Aug;146(8):3577-88
15878961
Endocrinology. 2009 Mar;150(3):1485-94
18988671
Cancer Res. 1994 Jul 15;54(14):3868-77
8033109
Oncogene. 2001 Apr 30;20(19):2390-400
11402335
Cell Cycle. 2004 Feb;3(2):145-8
14712077
J Clin Pathol. 2001 Aug;54(8):624-30
11477119
Breast Cancer Res Treat. 1999 Feb;53(3):217-27
10369068
Proc Natl Acad Sci U S A. 1998 Jan 20;95(2):696-701
9435255
Mol Cell Biol. 2007 Jan;27(2):466-80
17074804
Lab Invest. 1990 Mar;62(3):244-78
2107367
Endocrinology. 2007 May;148(5):2290-300
17317767
Science. 2000 Sep 8;289(5485):1751-4
10976068
Nature. 2010 Nov 4;468(7320):103-7
20881963
Breast Cancer Res Treat. 2009 Nov;118(1):161-8
19205874
Proc Natl Acad Sci U S A. 2007 Mar 27;104(13):5455-60
17369357
Breast Cancer Res Treat. 2006 Mar;96(2):131-46
16261397
Cancer Res. 2006 May 15;66(10):5304-13
16707456
Steroids. 2003 Nov;68(10-13):789-94
14667969