Journal
CANCER RESEARCH
Volume 70, Issue 24, Pages 10224-10233Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-10-3057
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Funding
- NIDDK [RO1 DK066110-01, W81XWH-08-1-0377]
- Department of Defense [RO1 DK066110-01, W81XWH-08-1-0377]
- National Institute of Environment Health Science [U01 ES/CA 012800]
- National Cancer Institute, National Institutes of Health, Department of Health and Human Services
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Estrogen receptor-positive and progesterone receptor-negative (ER+/PR-) breast cancers account for 15% to 25% of all human breast cancers and display more aggressive malignant characteristics than ER+/PR+ cancers. However, the molecular mechanism underlying development of ER+/PR- breast cancers still remains elusive. We show here that Tip30 deletion dramatically accelerated the onset of mammary tumors in the MMTV-Neu mouse model of breast cancer. The mammary tumors arising in Tip30(-/-) /MMTV-Neu mice were exclusively ER+/PR-. The growth of these ER+/PR- tumors depends not only on estrogen but also on progesterone despite the absence of detectable PR. Tip30 is predominantly expressed in ER+ mammary epithelial cells, and its deletion leads to an increase in the number of phospho-ER alpha-positive cells in mammary glands and accelerated activation of Akt in MMTV-Neu mice. Moreover, we found that Tip30 regulates the EGFR pathway through controlling endocytic downregulation of EGFR protein level and signaling. Together, these findings suggest a novel mechanism in which loss of Tip30 cooperates with Neu activation to enhance the activation of Akt signaling, leading to the development of ER+/PR- mammary tumors. Cancer Res; 70(24); 10224-33. (C) 2010 AACR.
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