TY - JOUR
T1 - Intraductal fulvestrant for therapy of ERα-positive ductal carcinoma in situ of the breast
T2 - A preclinical study
AU - Wang, Guannan
AU - Chen, Chuang
AU - Pai, Priya
AU - Korangath, Preethi
AU - Sun, Shengrong
AU - Merino, Vanessa F.
AU - Yuan, Jingping
AU - Li, Suping
AU - Nie, Guangjun
AU - Stearns, Vered
AU - Sukumar, Saraswati
N1 - Funding Information:
The Susan Love Research Foundation, the Fetting Fund for Breast Cancer Prevention and the Rubenstein Family Funds (to S.S). Conflicts of Interest Statement: The researchers claim no conflicts of interests.
Publisher Copyright:
© 2019 The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2019/7/1
Y1 - 2019/7/1
N2 - Mammographic screening for breast cancer has led to increased detection of ductal carcinoma in situ (DCIS) and a reappraisal of the necessity of aggressive treatment with their attendant toxicities for a preneoplastic lesion. Fulvestrant, a selective estrogen receptor degrader, is very effective in the treatment of estrogen receptor positive (ER+) breast cancer, but delivery by the painful intramuscular (i.m) route is limiting. We hypothesized that intraductal (i.duc) administration of fulvestrant will provide a direct, safe and effective treatment for DCIS. Mice bearing mammary ductal xenografts of ER+, luciferase-tagged MCF-7 breast cancer cells were administered vehicle or fulvestrant i.m or i.duc. I.duc MCF-7-luc tumors in mice treated with fulvestrant i.duc or i.m grew significantly slower than vehicle control. Whole mount analysis and histopathology showed that i.duc fulvestrant achieved significantly larger cancer-free areas. Western blot analysis showed reduced levels of estrogen receptor alpha (ERα) and its downstream targets, c-Myc and Cyclin D1, and increased levels of ERβ, which is known to inhibit ERα function. Immunohistochemical analysis of tumor sections showed that Ki67 and ERα protein levels decreased by 3-fold, and neoangiogenesis was inhibited by i.duc fulvestrant treatment. I.duc fulvestrant also reduced outgrowth of ERα+, autochthonous N-methyl-N-nitrosourea-induced mammary tumors in rats. Overall, we have shown that i.duc fulvestrant was significantly more effective than, or equivalent in action to i.m fulvestrant in two preclinical models of breast cancer. These studies provide evidence for a novel and safe route for fulvestrant therapy of DCIS and prevention of breast cancer. This preclinical study provides a strong basis for conducting clinical trials for DCIS and early breast cancer.
AB - Mammographic screening for breast cancer has led to increased detection of ductal carcinoma in situ (DCIS) and a reappraisal of the necessity of aggressive treatment with their attendant toxicities for a preneoplastic lesion. Fulvestrant, a selective estrogen receptor degrader, is very effective in the treatment of estrogen receptor positive (ER+) breast cancer, but delivery by the painful intramuscular (i.m) route is limiting. We hypothesized that intraductal (i.duc) administration of fulvestrant will provide a direct, safe and effective treatment for DCIS. Mice bearing mammary ductal xenografts of ER+, luciferase-tagged MCF-7 breast cancer cells were administered vehicle or fulvestrant i.m or i.duc. I.duc MCF-7-luc tumors in mice treated with fulvestrant i.duc or i.m grew significantly slower than vehicle control. Whole mount analysis and histopathology showed that i.duc fulvestrant achieved significantly larger cancer-free areas. Western blot analysis showed reduced levels of estrogen receptor alpha (ERα) and its downstream targets, c-Myc and Cyclin D1, and increased levels of ERβ, which is known to inhibit ERα function. Immunohistochemical analysis of tumor sections showed that Ki67 and ERα protein levels decreased by 3-fold, and neoangiogenesis was inhibited by i.duc fulvestrant treatment. I.duc fulvestrant also reduced outgrowth of ERα+, autochthonous N-methyl-N-nitrosourea-induced mammary tumors in rats. Overall, we have shown that i.duc fulvestrant was significantly more effective than, or equivalent in action to i.m fulvestrant in two preclinical models of breast cancer. These studies provide evidence for a novel and safe route for fulvestrant therapy of DCIS and prevention of breast cancer. This preclinical study provides a strong basis for conducting clinical trials for DCIS and early breast cancer.
UR - http://www.scopus.com/inward/record.url?scp=85070181850&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85070181850&partnerID=8YFLogxK
U2 - 10.1093/carcin/bgz084
DO - 10.1093/carcin/bgz084
M3 - Article
C2 - 31046118
AN - SCOPUS:85070181850
SN - 0143-3334
VL - 40
SP - 903
EP - 913
JO - Carcinogenesis
JF - Carcinogenesis
IS - 7
ER -