Rab11-FIP1C is a critical negative regulator in ErbB2-mediated mammary tumor progression

Pierre Luc Boulay, Louise Mitchell, Jason Turpin, Julie Émilie Huot-Marchand, Cynthia Lavoie, Virginie Sanguin-Gendreau, Laura Jones, Shreya Mitra, Julie M. Livingstone, Shirley Campbell, Michael Hallett, Gordon B. Mills, Morag Park, Lewis Chodosh, Douglas Strathdee, Jim C. Norman, William J. Muller

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

Rab coupling protein (FIP1C), an effector of the Rab11 GTPases, including Rab25, is amplified and overexpressed in 10% to 25% of primary breast cancers and correlates with poor clinical outcome. Rab25 is also frequently silenced in triplenegative breast cancer, suggesting its ability to function as either an oncogene or a tumor suppressor, depending on the breast cancer subtype. However, the pathobiologic role of FIP family members, such as FIP1C, in a tumor-specific setting remains elusive. In this study, we used ErbB2 mouse models of human breast cancer to investigate FIP1C function in tumorigenesis. Doxycycline-induced expression of FIP1C in the MMTV-ErbB2 mouse model resulted in delayed mammary tumor progression. Conversely, targeted deletion of FIP1C in the mammary epithelium of an ErbB2 model coexpressing Cre recombinase led to accelerated tumor onset. Genetic and biochemical characterization of these FIP1C-proficient and -deficient tumor models revealed that FIP1C regulated E-cadherin (CDH1) trafficking and ZONAB (YBX3) function in Cdk4-mediated cell-cycle progression. Furthermore, we demonstrate that FIP1C promoted lysosomal degradation of ErbB2. Consistent with our findings in the mouse, the expression of FIP1C was inversely correlated with ErbB2 levels in breast cancer patients. Taken together, our findings indicate that FIP1C acts as a tumor suppressor in the context of ErbB2-positive breast cancer and may be therapeutically exploited as an alternative strategy for targeting aberrant ErbB2 expression.

Original languageEnglish (US)
Pages (from-to)2662-2674
Number of pages13
JournalCancer Research
Volume76
Issue number9
DOIs
StatePublished - May 1 2016
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Boulay, P. L., Mitchell, L., Turpin, J., Huot-Marchand, J. É., Lavoie, C., Sanguin-Gendreau, V., Jones, L., Mitra, S., Livingstone, J. M., Campbell, S., Hallett, M., Mills, G. B., Park, M., Chodosh, L., Strathdee, D., Norman, J. C., & Muller, W. J. (2016). Rab11-FIP1C is a critical negative regulator in ErbB2-mediated mammary tumor progression. Cancer Research, 76(9), 2662-2674. https://doi.org/10.1158/0008-5472.CAN-15-2782