Currently, Tamoxifen and Aromatase inhibitors are used for prevention of estrogen receptor positive (ER+) breast cancer; however, there is no effective prevention strategy for ER- breast cancer. HER2 overexpression (HER2+) can be detected in up to 60% early stage breast lesions, such as atypical hyperplasia (ADH) and ductal carcinoma in situ (DCIS). Up to 40% of ER- breast cancers are HER2+. Thus, targeting HER2 signaling may be an effective chemoprevention strategy for these ER- and HER2+ breast cancer. Here, we stable introduced ErbB2-expressing retroviruses into the ER-, non-transformed MCF10A cells (MCF10A.B2) to establish an ER- and HER2+ early breast disease model. We show that Lapatinib, a FDA-approved dual tyrosine kinase inhibitor for both HER2 and EGFR, reduced the proliferation rate and increased the apoptosis in MCF10A.B2 cells. In 3D culture, Lapatinib treatment starting at day 6 prevented the MCF10A.B2 cells from forming abnormal acini, and the numbers of DCIS-like acini have been significantly decreased compared to control group. Untreated MCF10A.B2 cells forms DCIS-like acini in 3D culture by day 10, which have been reverted to normal or ADH-like acini when lapatinib treatment started by day 10. Furthermore, MMTV-neu mouse model develop ER- mammary tumors in 6.4 months, whereas lapatinib treatment (30mg/kg/day, six days per week) starting at 10 weeks of age significantly delayed the tumor initiation and progression in this mouse model as detected by mammary gland biopsy and fiber optic micro-endoscope (FOME) imaging. Mice treated with lapatinib had fewer premalignant lesions and reduced noninvasive tumors in their mammary glands, which are correlated with reduced proliferation rate and increased apoptosis rate, indicating that lapatinib is a promising agent for the prevention/intervention of ER- and HER2+ breast cancers. To identify effective and reliable biomarkers to assess the risk of ER-/HER2+ lesions and efficacy of lapatinib for prevention and intervention, cDNA microarray and reverse phase protein array (RPPA) were performed on MCF10A.B2 cells and control MCF10A cells. We have identified several molecular pathways activated by HER2+ in this model which will be tested for their roles in the initiation of mammary tumors and as potential targets for prevention of ER-/HER2+ breast disease. Our study brings better understanding of the mechanism underlying ER-/HER2+ early stage breast disease progression to cancer and could be rapidly translated into the clinic for prevention of ER-/HER2+ breast cancers.
Citation Format: Jia Xu, Shalini Jain, Dihua Yu. Prevention of HER2 overexpressing early stage breast disease progression by lapatinib. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2137. doi:10.1158/1538-7445.AM2014-2137