Our study indicates that blocking PI3K pathway activation mediated by HER-2/neu overexpression may be useful in the treatment of breast tumors with HER-2/neu overexpression and wild-type p53.
We screened 250 primary human breast tumors for mutations in PIK3CA in order to determine associations with pathological features and with patient outcome.
In comparing deregulation of oncogenic pathways between age groups, a higher probability of PI3K (p = 0.006) and Myc (p = 0.03) pathway deregulation was observed in breast tumors arising in younger women.
In this study, we found that VEGF-A 165 (recombinant protein or breast tumor cell-secreted) is also capable of inducing migration of VEGFR2-negative human aortic smooth muscle cells (hAOSMCs), and this induction is mediated through a molecular cross-talk of neuropilin-1 (NRP-1), VEGFR1 (Flt-1), and phosphoinositide 3-kinase (PI3K)/Akt signaling kinase.
PIK3CA mutations are not associated with altered sensitivity to preoperative anthracycline-based or taxane-based chemotherapies in ER-positive and ER-negative breast tumors.
AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P < 0.0001, respectively).
However, here we show through phosphoprotein profiling and functional genomic studies that many PIK3CA mutant cancer cell lines and human breast tumors exhibit only minimal AKT activation and a diminished reliance on AKT for anchorage-independent growth.
We screened papillary breast neoplasms for activating point mutations in PIK3CA, AKT1, and RAS protein-family members, which are common in invasive ductal carcinomas.
Using reverse-phase protein microarrays, we identified a breast tumor protein signature of PI3K pathway activation that predicted poor outcome after adjuvant endocrine therapy in patients.
Our results suggest that mutation of PIK3CA is an early event in breast cancer that is more likely to play a role in breast tumor initiation than in invasive progression, although a potential role for exon 9 mutations in the progression of a subset of DCIS cases cannot be excluded.
By using these signatures, we scored each ER+ breast tumor represented in multiple independent expression-profiling datasets (four mRNA, n = 915; one protein, n = 429) for activation of the PI3K pathway.
These data demonstrate that the RAS pathway signature is superior to KRAS mutation status for the prediction of dependence on RAS signaling, can predict response to PI3K and RAS pathway inhibitors, and is likely to have the most clinical utility in lung and breast tumors.
These data suggest that activation of the ERBB2-PI3K-AKT pathway by loss of PTEN at early stages of tumorigenesis promotes the formation of breast tumors with apocrine features.
The activation of the oncogene PIK3CA and the loss of regulators of AKT including the tumor suppressor gene PTEN are mutations commonly found in breast tumors.
Our results suggest that the PIK3CAH1047R oncogene targets a multipotent progenitor cell and, furthermore, show that this model recapitulates features of human breast tumors with PIK3CAH1047R.
The purpose of this work was to determine whether there are differences in PIK3CA mutation status and PTEN protein expression between primary and matched metastatic breast tumors as this could influence patient management.
Available paired tissue samples from breast tumors known to harbor mutations underwent massARRAY genotyping (n = 70) to identify PIK3CA and AKT1(E17K) mutations.
Somatic mutations in phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) are frequent in breast tumours and have been associated with oestrogen receptor (ER) expression, human epidermal growth factor receptor-2 overexpression, lymph node metastasis and poor survival.
In particular, mutations in the gene PIK3CA that encodes the p110α catalytic subunit of the PI3K enzymes result in cell proliferation and resistance to apoptosis in vitro and induce breast tumors in transgenic mice.