| First Author | Simond AM | Year | 2017 |
| Journal | Oncogene | Volume | 36 |
| Issue | 43 | Pages | 6059-6066 |
| PubMed ID | 28783168 | Mgi Jnum | J:247760 |
| Mgi Id | MGI:5926649 | Doi | 10.1038/onc.2017.264 |
| Citation | Simond AM, et al. (2017) ErbB2-positive mammary tumors can escape PI3K-p110alpha loss through downregulation of the Pten tumor suppressor. Oncogene 36(43):6059-6066 |
| abstractText | Breast cancer is the most common cancer among women and 30% of patients will be diagnosed with an ErbB2-positive tumor. Forty percent of ErbB2-positive breast tumors have an activating mutation in p110alpha, a catalytic subunit of phosphoinositide 3-kinase. Clinical and experimental data show that breast tumors treated with a p110alpha-specific inhibitor often circumvent inhibition and resume growth. To understand this mechanism of resistance, we crossed a p110alpha conditional (p110alphaflx/flx) mouse model with mice that overexpress the ErbB2/Neu-IRES-Cre transgene (NIC) specifically in the mammary epithelium. Although mammary-specific deletion of p110alpha dramatically delays tumor onset, tumors eventually arise and are dependent on p110beta. Through biochemical analyses we find that a proportion of p110alpha-deficient tumors (23%) display downregulation of the Pten tumor suppressor. We further demonstrate that loss of one allele of PTEN is sufficient to shift isoform dependency from p110alpha to p110beta in vivo. These results provide insight into the molecular mechanism by which ErbB2-positive breast cancer escapes p110alpha inhibition. |
