Src, p53 and estrogen receptor-positive breast cancer

Project: Research project

Description

Most breast cancers, have increased levels of the tyrosine kinase Src, which has been postulated to promote
oncogenic signaling by both growth factor and hormone receptors, as well as to facilitate both survival and
invasive behavior. In addition, inhibition of Src has been proposed as a mechanism to restore sensitivity to
trastuzumab (in the case of Her2 positive tumors) and tamoxifen (in the case of ER/PR+ tumors). Yet clinical
trials in breast cancer with multi-targeted kinase inhibitors that inhibit Src (dasatinib, bosutinib and saracatinib)
have yet to meet with great success. For example, a recent phase II trial of dasatinib in progressive advanced
breast cancer showed disease control in 19% of patients with ER/PR+ tumors, with no responses noted in
Her2+ or triple negative tumors. One notable difference between ER+ and other breast cancers is that p53
mutation is much less common in the former than the latter. It is also known that loss of p53 function leads to a
worse outcome in breast cancer. Using mesenchymal cells as a model system, we have previously shown that
Src family kinases (SFKs) are required for mitogenesis elicited by a variety of growth factors, including PDGF
and EGF. In addition, we have determined that SFKs are required to overcome a cell cycle block controlled by
p53: if p53 is absent or mutated, SFKs are no longer necessary for mitogenic signaling. We have confirmed a
requirement for SFKs for G1>S progression of breast cancer cells in response to estrogen. We hypothesize
that Src is required for tumor cell growth only in those breast cancers with functional p53, and predict that p53
status will dictate how breast cancers will respond to Src inhibitors. The outline of our hypothesis is shown in
the schematic. Here we will focus on the effects of ER-activated Src, and for this proposal, not evaluate the
genomic and transcription factor crosstalk effects of the estrogen receptor. To test our hypothesis, we will
determine the effect of p53 status on the response of ER+ve tumor cells to Src inhibitors, and evaluate the
effect of Src inhibition on signaling events downstream of ER.
There are several innovative aspects to this proposal, including the first demonstration that p53 status can
affect SFK-dependent cell cycle progression of a human cancer cell, and the use of the understudied SFK
inhibitor SU11333 both in vitro and in vivo. The outcome of this research will be a more complete
understanding of the role of Src in ER+ve breast cancer progression, and how p53 status might affect this.
This would set the stage for more in depth analyses of the signaling pathways involved. Furthermore, if our
hypothesis is correct, this would have potential clinical impact, and might justify the continued testing of Src
inhibitors in ER+ve breast cancer. More broadly, the data might also justify determining p53 status during
enrollment in Src inhibitor studies in other cancer types.
StatusFinished
Effective start/end date9/15/148/31/16

Funding

  • National Institutes of Health: $200,970.00
  • National Institutes of Health: $167,475.00

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Estrogen Receptors
Breast Neoplasms
src-Family Kinases
Neoplasms
Phosphotransferases
Cell Cycle
Somatotropin Receptors
Growth Factor Receptors
Tamoxifen
Epidermal Growth Factor
Intercellular Signaling Peptides and Proteins
Estrogens
Transcription Factors
Outcome Assessment (Health Care)
Survival
Growth

ASJC

  • Medicine(all)