Format

Send to

Choose Destination
See comment in PubMed Commons below
Am J Pathol. 2009 Mar;174(3):1065-74. doi: 10.2353/ajpath.2009.080719. Epub 2009 Jan 29.

Prolactin-growth factor crosstalk reduces mammary estrogen responsiveness despite elevated ERalpha expression.

Author information

1
Department of Comparative Biosciences, University of Wisconsin, 2015 Linden Dr., Madison, WI 53706, USA.

Abstract

Most breast cancers that occur in women express estrogen receptor alpha (ERalpha). However, a large subset of these cancers either does not initially respond to anti-estrogen therapy or develops resistance to such treatment modalities. One postulated mechanism of this failure is signaling cross talk between hormones and local growth factors. To examine these complex interactions in vivo, we assessed the effects of estrogen on transforming growth factor alpha (TGFalpha)- and prolactin (PRL)-induced mammary tumorigenesis in transgenic mice. Both PRL and estrogen reduced the latency of TGFalpha-induced oncogenesis, resulting in tumors that were variably ERalpha-positive, but were progesterone receptor-negative. However, despite elevated ERalpha levels in NRL-PRL/TGFalpha glands, tumor latency was not reduced with increasing estrogen levels, nor increased after ovariectomy. Furthermore, PRL and TGFalpha in combination blocked the mitogenic effects of estrogen, dramatically reduced progesterone receptor levels, and diminished ERalpha down-regulation in response to circulating estrogen levels, in contrast to the other genotypes. Notably, however, ductal morphology remained responsive to estrogen, indicating that TGFalpha and PRL in combination can inhibit some, but not all, estrogenic signals. Both in vitro and in vivo, PRL and TGFalpha cooperatively enhanced Akt phosphorylation, which is associated with endocrine resistance in human disease. These findings provide insight into the interactions of PRL with growth factors during mammary oncogenesis and suggest combinatorial approaches that may result in improved therapeutic efficacy.

PMID:
19179608
PMCID:
PMC2665765
DOI:
10.2353/ajpath.2009.080719
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Elsevier Science Icon for PubMed Central
    Loading ...
    Support Center