Hormone-induced protection against mammary tumorigenesis is conserved in multiple rat strains and identifies a core gene expression signature induced by pregnancy.
Women who have their first child early in life have a substantially lower lifetime risk of breast cancer. The mechanism for this is unknown. Similar to humans, rats exhibit parity-induced protection against mammary tumorigenesis. To explore the basis for this phenomenon, we identified persistent pregnancy-induced changes in mammary gene expression that are tightly associated with protection against tumorigenesis in multiple inbred rat strains. Four inbred rat strains that exhibit marked differences in their intrinsic susceptibilities to carcinogen-induced mammary tumorigenesis were each shown to display significant protection against methylnitrosourea-induced mammary tumorigenesis following treatment with pregnancy levels of estradiol and progesterone. Microarray expression profiling of parous and nulliparous mammary tissue from these four strains yielded a common 70-gene signature. Examination of the genes constituting this signature implicated alterations in transforming growth factor-beta signaling, the extracellular matrix, amphiregulin expression, and the growth hormone/insulin-like growth factor I axis in pregnancy-induced alterations in breast cancer risk. Notably, related molecular changes have been associated with decreased mammographic density, which itself is strongly associated with decreased breast cancer risk. Our findings show that hormone-induced protection against mammary tumorigenesis is widely conserved among divergent rat strains and define a gene expression signature that is tightly correlated with reduced mammary tumor susceptibility as a consequence of a normal developmental event. Given the conservation of this signature, these pathways may contribute to pregnancy-induced protection against breast cancer.
Blakely
Collin M
CM
Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104-6160, USA.
Stoddard
Alexander J
AJ
Belka
George K
GK
Dugan
Katherine D
KD
Notarfrancesco
Kathleen L
KL
Moody
Susan E
SE
D'Cruz
Celina M
CM
Chodosh
Lewis A
LA
D066258:Amphiregulin; D000818:Animals; D066255:EGF Family of Proteins; D005260:Female; D015870:Gene Expression; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000096:biosynthesis / Q000235:genetics; D013006:Growth Hormone / Q000096:biosynthesis / Q000235:genetics; D006728:Hormones / Q000096:biosynthesis / Q000235:genetics*; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics; D008321:Mammary Glands, Animal; D008325:Mammary Neoplasms, Experimental / Q000235:genetics* / Q000378:metabolism / Q000517:prevention & control; D051379:Mice; D020411:Oligonucleotide Array Sequence Analysis; D010298:Parity; D011247:Pregnancy; D011270:Pregnancy, Animal / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000235:genetics; D053782:Transforming Growth Factor beta3; D015854:Up-Regulation
C587848:AREG protein, human; D066258:Amphiregulin; C587849:Areg protein, mouse; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D006023:Glycoproteins; D006728:Hormones; D036341:Intercellular Signaling Peptides and Proteins; C509045:Tgfb3 protein, mouse; C509046:Tgfb3 protein, rat; D016212:Transforming Growth Factor beta; D053782:Transforming Growth Factor beta3; D013006:Growth Hormone