Breast cancer is a leading cause of cancer death among women. Current strategies to combat breast cancer mainly target late stage malignancies to extend lifespan;consequently, they often fail to result in disease free survival. While detection of pre-malignant lesions is increasingly accurate, the inability to predict which precancerous lesions lead to neoplastic growth has impeded efforts to identify patients that are likely to develop aggressive neoplasms or drugs to prevent this. This study addresses this issue by defining how the early loss of cellular differentiation is coordinated with the induction of aberrant proliferation by the adaptor protein Amot. Because the breakdown of the apical polarity is one of the earliest essential steps for cells to be sensitized to pro-growth signaling, such studies may explain how highly proliferative breast cancer cells that utilize ErbB type receptor tyrosine kinases for growth are formed. Our model relating these effects to a cellular mechanism posits that polarity proteins induce the prolonged activation of MAPKs. This is consistent with several reports that Ras and Erk1/2 must be targeted to endosomes to undergo prolonged activation that is required for cellular proliferation. The implications of this model for promoting the formation and progression of ErbB2 and triple negative type breast cancers will be investigated.

Public Health Relevance

A majority of the 40,000 mortalities from breast cancer each year follow therapeutic strategies that target late stage malignant tumors. The premise of this proposal is that long-term survival could be substantially improved if early hyperplastic lesions were prevented from developing into aggressive cancers;a process that is mainly characterized by the loss of epithelial architecture and aberrant cellular accumulation. To this end, this study will investigate a novel mechanism whereby loss of cellular shape directly regulates cell growth to promote early initiation of cellular proliferation and invasiveness.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA151765-03
Application #
8462574
Study Section
Tumor Progression and Metastasis Study Section (TPM)
Program Officer
Ault, Grace S
Project Start
2011-07-01
Project End
2016-04-30
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$293,799
Indirect Cost
$98,749
Name
Indiana University-Purdue University at Indianapolis
Department
Biochemistry
Type
Schools of Medicine
DUNS #
603007902
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
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