Abstract 1388: Luminal breast cancer metastasis is hormone-dependent and progesterone activates dormant disease.
Authors: Ogba Ndiya , Manning Nicole , Bliesner Brian , Ambler Kelly , Haughian James , Pinto Mauricio , Horwitz Kathryn B. 
Published: August 2014

Luminal, estrogen (ER) and/or progesterone (PR) receptor-positive breast cancers are the least aggressive forms of the disease. However, luminal cancers are the most common (70-80%) breast cancer subtype and therefore overall responsible for the greatest number of deaths due to metastases. The role of estrogens (E) in promoting breast cancer growth is well known. In contrast, little is known about the role of E or progesterone (P) in breast cancer metastasis. Most metastasis models use ER-PR- basal-like cells in which the role of women's hormones cannot be studied. We have generated a metastasis model in ovariectomized immune- compromised mice using 100,000 human luminal or basal-like breast cancer cells injected directly into the arterial circulation. Tumor cells were simultaneously tagged with luciferase and ZsGreen to quantify whole-body metastatic burden in vivo and organ-specific metastases at necropsy. Mice were untreated (control), or supplemented with physiological concentrations of E or E+P (n=10/group). To avoid effects due to genetic variation, we used two new isogenic sublines of luminal T47D cells in our studies: E3, which are ER+PR+ and EWD8, which are identical but ER-PR-. We also tested luminal MCF-7 cells and basal MDA-231 cells. 1. Due to extensive metastases, survival of ER-PR- EWD8 or MDA-231-injected mice was brief (25-45 days) regardless of hormone treatment. 2. In contrast, luminal E3 or MCF-7-injected control mice appeared to be metastasis-free and were long-lived. However, E or E+P supplementation promoted luminal tumor metastasis. P was not protective; rather it tended to enhance metastatic burden, especially in E3 cells. 3. Major sites of luminal metastases in hormone-replete mice were bone, liver, lung and brain, analogous to sites seen clinically. 4. We performed a study in which mice injected with luminal tumor cells were maintained under control conditions for 8 weeks with no evidence of metastasis. They were then switched to E or E+P. E alone had no effect, but E+P activated metastasis in approximately 30% of mice. This suggests that a reservoir of dormant luminal metastatic cells remain sequestered in control tissues that under estrogenized conditions can be activated by P. 5. In luminal bone metastases, P significantly enhanced expression of cells that lack ER and PR, but express the basal-like maker cytokeratin 5 (CK5). The proliferation rate of the CK5+ subpopulation was markedly reduced compared to their ER+PR+ neighbors. Conclusions: E and P promote luminal breast cancer metastasis, may reactivate dormant disease at metastatic sites, and stimulate expression of an ER-PR- metastatic tumor-cell subpopulation that would be resistant to hormone therapies.

Support: Department of Defense Breast Cancer Research Program, National Institute of Health CA026869-33, and the Breast Cancer Research Foundation.

Citation Format: Ndiya Ogba, Nicole Manning, Brian Bliesner, Kelly Ambler, James Haughian, Mauricio Pinto, Kathryn B. Horwitz. Luminal breast cancer metastasis is hormone-dependent and progesterone activates dormant disease. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1388. doi:10.1158/1538-7445.AM2013-1388