Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer

Hyun Jung Kim, Xiaojiang Cui, Susan G. Hilsenbeck, Adrian V. Lee, Mitch Dowsett, Kathleen Pritchard, Steven Come, James Ingle, Soonmyung Paik, Aman Buzdar, Carlos Arteaga

Research output: Contribution to journalArticle

43 Scopus citations

Abstract

Response to endocrine therapy in breast cancer correlates with estrogen receptor (ER) and progesterone receptor (PR) status. It was originally hypothesized that the ability of PR to predict response to endocrine therapy was due to the fact that PR is an estrogen-regulated gene and that its levels represented a marker of functional ER activity. However, it is now known that loss of PR can occur via multiple mechanisms, many of which do not include ER function, e.g., hypermethylation of the PR promoter and loss of heterozygosity of the PR gene. We have shown that growth factor signaling pathways can directly down-regulate PR levels via the phosphatidylinositol 3′-kinase (PI3K)/Akt/mTOR pathway, and that this can occur independent of ER. For example, overexpression of myr-Akt in MCF-7 cells causes complete loss of PR protein and mRNA but does not reduce ER levels or activity, thus generating ER+/PR- MCF-7 cells. Therefore, the absence of PR may not simply reflect a lack of ER activity but rather may reflect hyperactive cross-talk between ER and growth factor signaling pathways. Consistent with this hypothesis, several recent clinical studies have found that ER+/PR- breast cancers overexpress human epidermal growth factor receptor (HER) 1 and HER2 compared with ER+/PR+ breast cancers. Although HER receptors can lower ER levels, one study showed that loss of PR correlated with high HER2 levels in a multivariate analysis. Furthermore, loss of PTEN, a negative regulator of the PI3K/Akt signaling pathway, has been shown to be associated with specific loss of PR and no change in ER levels. Given the well-recognized resistance of ER+/PR- breast cancer to antiestrogens, more studies are needed to better understand the etiology of ER+/PR- breast cancer, particularly the analysis of other growth factor receptors and their downstream signaling intermediates with respect to PR status.

Original languageEnglish (US)
Pages (from-to)1013s-1018s
JournalClinical Cancer Research
Volume12
Issue number3 II
DOIs
StatePublished - Feb 1 2006

    Fingerprint

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Kim, H. J., Cui, X., Hilsenbeck, S. G., Lee, A. V., Dowsett, M., Pritchard, K., Come, S., Ingle, J., Paik, S., Buzdar, A., & Arteaga, C. (2006). Progesterone receptor loss correlates with human epidermal growth factor receptor 2 overexpression in estrogen receptor-positive breast cancer. Clinical Cancer Research, 12(3 II), 1013s-1018s. https://doi.org/10.1158/1078-0432.CCR-05-2128