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 p110α, a catalytic subunit of phosphoinositide 3-kinase. Clinical and experimental data show that breast tumors treated with a p110α-specific inhibitor often circumvent inhibition and resume growth. To understand this mechanism of resistance, we crossed a p110α conditional (p110αflx/flx) mouse model with mice that overexpress the ErbB2/Neu-IRES-Cre transgene (NIC) specifically in the mammary epithelium. Although mammary-specific deletion of p110α dramatically delays tumor onset, tumors eventually arise and are dependent on p110β. Through biochemical analyses we find that a proportion of p110α-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 p110α to p110β in vivo. These results provide insight into the molecular mechanism by which ErbB2-positive breast cancer escapes p110α inhibition.
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We would like to thank Cynthia Lavoie for assistance with the GDC-0941 drug trial and Vasilios Papavasiliou for mammary fat pad injections and transplants; Colin Ratcliffe for technical support with the Metamorph software; Chen Ling for editorial assistance and all the students in the Muller laboratory for their constant feedback and support. Our work is supported by the Canadian Institutes of Health Research (CIHR): MOP-133706 (WJM), FDN-148373 (WJM), Terry Fox team program grant: RI X-242115 (WJM). WJM is supported by CRC Chair in Molecular Oncology. National Institutes of Health (NIH): P50 CA168504 (JJZ), CA187918-02 (JJZ), R35 CA210057 (JJZ), CA172461 (JJZ) and Breast Cancer Research Foundation (JJZ), Roland and Marcel Gosselin Fellowship (AMS).
The authors declare no conflict of interest.
Supplementary Information accompanies this paper on the Oncogene website
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