IGF-2 is a mediator of prolactin-induced morphogenesis in the breast.
The mechanisms by which prolactin controls proliferation of mammary epithelial cells (MECs) and morphogenesis of the breast epithelium are poorly understood. We show that cyclin D1(-/-) MECs fail to proliferate in response to prolactin and identify IGF-2 as a downstream target of prolactin signaling that lies upstream of cyclin D1 transcription. Ectopic IGF-2 expression restores alveologenesis in prolactin receptor(-/-) epithelium. Alveologenesis is retarded in IGF-2-deficient MECs. IGF-2 and prolactin receptor mRNAs colocalize in the mammary epithelium. Prolactin induces IGF-2 mRNA and IGF-2 induces cyclin D1 protein in primary MECs. Thus, IGF-2 is a mediator of prolactin-induced alveologenesis; prolactin, IGF-2, and cyclin D1, all of which are overexpressed in breast cancers, are components of a developmental pathway in the mammary gland.
Brisken
Cathrin
C
Department of Surgical Oncology, Harvard Medical School and Massachusetts General Hospital, Boston, MA 02114, USA. cathrin.brisken@isrec.unil.ch
Ayyannan
Ayyakkannu
A
Nguyen
Cuc
C
Heineman
Anna
A
Reinhardt
Ferenc
F
Tan
Jian
J
Dey
S K
SK
Dotto
G Paolo
GP
Weinberg
Robert A
RA
Jan
Tian
T
D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics; D002277:Carcinoma / Q000235:genetics; D002352:Carrier Proteins; D002455:Cell Division / Q000235:genetics*; D002478:Cells, Cultured; D019938:Cyclin D1 / Q000172:deficiency* / Q000235:genetics; D004847:Epithelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D005796:Genes / Q000187:drug effects / Q000235:genetics; D005820:Genetic Testing; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism*; D008321:Mammary Glands, Animal / Q000166:cytology / Q000196:embryology* / Q000378:metabolism; D008562:Membrane Glycoproteins; D051379:Mice; D018345:Mice, Knockout; D020411:Oligonucleotide Array Sequence Analysis; D011374:Progesterone / Q000378:metabolism / Q000494:pharmacology; D011388:Prolactin / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D011980:Receptors, Progesterone; C505687:Tnfrsf11a protein, mouse; C505689:Tnfsf11 protein, mouse; D019938:Cyclin D1; D011374:Progesterone; D007335:Insulin-Like Growth Factor II; D011388:Prolactin