Insulin-Like Growth Factor-I Inhibits Progesterone Receptor Expression in Breast Cancer Cells via the Phosphatidylinositol 3-Kinase/Akt/Mammalian Target of Rapamycin Pathway: Progesterone Receptor as a Potential Indicator of Growth Factor Activity in Breast Cancer

Abstract

Although interactions between estrogen and growth factor signaling pathways have been studied extensively, how growth factors and progesterone regulate each other is less clear. In this study, we found that IGF-I sharply lowers progesterone receptor (PR) mRNA and protein levels in breast cancer cells. Other growth factors, such as epidermal growth factor, also showed the same effect. The decrease of PR levels was associated with reduced PR activity. Unlike progestins, IGF-I does not utilize the proteasome for down-regulating PR. Instead, the IGF-I-mediated decrease in PR levels is via an inhibition of PR gene transcription. In addition, the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway was found to be specifically involved in this IGF-I effect. Our data also suggest that the IGF-I down-regulation of PR is not mediated via a reduction of estrogen receptor (ER) levels or activity. First, IGF-I induced ligand-independent ER activity while reducing ER-dependent PR levels. Second, whereas PR and cyclin D1 are both ER up-regulated, IGF-I increased cyclin D1 levels while decreasing PR levels. Third, constitutively active PI3K or Akt induced ER activity but reduced PR levels and activity. Taken together, our data indicate that IGF-I inhibits PR expression in breast cancer cells via the PI3K/Akt/mTOR pathway. Because low or absent PR in primary breast cancer is associated with poor prognosis and response to hormone therapy, our results suggest that low PR status may serve as an indicator of activated growth factor signaling in breast tumor cells, and therefore of an aggressive tumor phenotype and resistance against hormonal therapy.

Coffee prevents early events in tamoxifen-treated breast cancer patients and modulates hormone receptor status

“…Phosphorylated Akt (pAkt) down-regulates PgR levels and activity and, in addition, induces ER ligand independent activity [27]. These results are consistent with the lower frequency of tumors with discordant ER and PgR status we found among patients with a moderate to high coffee consumption.…”

Vascular endothelial growth factor receptor 2 and downstream p38 mitogen-activated protein kinase are possible candidate markers of intrinsic resistance to adjuvant endocrine treatment in steroid receptor positive breast cancer

“…Expression of p38 was not correlated with later relapses, tumor stage or other breast cancer factors beside negative PgR a marker claimed to be part of intrinsic resistance [10,11]. Preclinical studies in ER - The major drawback of the present study is the small patient population, above all regarding p38 analyses, resulting in few events and less power in statistical analyses, unable to fully elucidate the role of p38 in endocrine resistance.…”

“…Examples of pathways involved in intrinsic resistance have been enhanced activity of EGFR or IGFR that result in an impaired estrogen induction of the PgR [10][11]27]. However, tyrosine kinase receptors have also shown a role in acquired resistance in preclinical studies [28].…”

“…Several RTK´s i.e., the insulin-like growth factor receptor (IGFR), the epidermal growth factor receptor (EGFR) as well as their downstream cascades has shown to be part of this process [10][11]. Also patients expressing significant levels of ER and/or PgR can have breast cancers that do not respond to endocrine therapy; either at the beginning of treatment (de novo or intrinsic resistance) or after prolonged use (acquired resistance).…”

A Review of an Unfavorable Subset of Breast Cancer: Estrogen Receptor Positive Progesterone Receptor Negative

“…In a multivariate analysis on primary breast cancer patients, Bardou et al [31] confirmed that PR was an independent predictor of response to endocrine therapy and that loss of PR was detrimental to the relative risk for recurrence (ER ϩ PR ϩ , 53%; ER ϩ PR Ϫ , 23%). The loss of PR in primary breast cancer is associated with faster disease progression and a poorer response to endocrine therapy [32].…”