Progesterone crosstalks with insulin-like growth factor signaling in breast cancer cells via induction of insulin receptor substrate-2.
Both progesterone and the insulin-like growth factors (IGFs) are critically involved in mammary gland development and also in breast cancer progression. However, how the progesterone and IGF signaling pathways interact with each other to regulate breast cancer cell growth remains unresolved. In this study, we investigated progesterone regulation of IGF signaling components in breast cancer cells. We found that insulin receptor substrate-2 (IRS-2) levels were markedly induced by progesterone and the synthetic progestin R5020 in MCF-7 and other progesterone receptor (PR) positive breast cancer cell lines, whereas IRS-1 and the IGF-I receptor were not induced. The antiprogestin RU486 blocked the R5020 effect on IRS-2 expression. Ectopic expression of either PR-A or PR-B in C4-12 breast cancer cells (estrogen receptor and PR negative) showed that progestin upregulation of IRS-2 was mediated specifically by PR-B. The IRS-2 induction by R5020 occurred via an increase of IRS-2 mRNA levels. Furthermore, progestin treatment prior to IGF-I stimulation resulted in higher tyrosine-phosphorylated IRS-2 levels, increased binding of IRS-2 to Grb-2 and the PI3K regulatory subunit p85, and correspondingly enhanced ERK and Akt activation, as compared with IGF-I-only conditions. Taken together, our data suggest that IRS-2 may play an important role in crosstalk between progesterone and the IGFs in breast cancer cells.
Cui
Xiaojiang
X
Breast Center, Baylor College of Medicine, Houston, TX 77030, USA.
Lazard
ZaWaunyka
Z
Zhang
Ping
P
Hopp
Torsten A
TA
Lee
Adrian V
AV
D001943:Breast Neoplasms / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006727:Hormone Antagonists / Q000494:pharmacology; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D015735:Mifepristone / Q000494:pharmacology; D010750:Phosphoproteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011374:Progesterone / Q000494:pharmacology*; D011372:Progestins / Q000494:pharmacology; D011397:Promegestone / Q000494:pharmacology; D020033:Protein Isoforms / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D011972:Receptor, Insulin / Q000378:metabolism*; D011980:Receptors, Progesterone / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D013002:Somatomedins / Q000187:drug effects / Q000378:metabolism*; D015854:Up-Regulation
D006727:Hormone Antagonists; C526297:IRS2 protein, human; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; D011372:Progestins; D020033:Protein Isoforms; D012333:RNA, Messenger; D011980:Receptors, Progesterone; D013002:Somatomedins; D015735:Mifepristone; D011374:Progesterone; D011397:Promegestone; D011972:Receptor, Insulin