AMPK activation via metformin enhances survival of clinically dormant residual ER+ breast tumor cells during estrogen deprivation therapy
Session type: Poster sessions
While adjuvant anti-estrogen therapies have shown immense benefit for the treatment of estrogen receptor (ER)-positive breast cancer (BC), ~30% of patients experience recurrence within 15 years of follow-up. Over half of these recurrence events occur after the standard five-year adjuvant treatment period, suggesting that ER+ BC cells undergo periods of clinical dormancy. Despite showing efficacy against recurrent/metastatic solid tumors, drugs sometimes fail to increase recurrence-free survival when given (neo)adjuvantly. The biology and microenvironments of overt tumors likely differ substantially from dormant cancer cells. The development of models to investigate clinically dormant disease will lead to improved understanding of residual tumor cell biology and ultimately improve rationale for adjuvant trials.
We developed novel xenograft models of clinical dormancy in ER+ BC. Low systemic levels of estrogens in mice can be further suppressed with ovariectomy, thus mimicking the effects of aromatase inhibitor(AI)-induced estrogen deprivation (ED). In ovariectomized mice, MCF-7/Luciferase cells form palpable tumors with 17b-estradiol supplementation. ED induced rapid tumor regression and decreased bioluminescent signal. However, a small proportion of ER+ BC cells survive ED for several months in a clinically dormant, growth-suppressed state.
RNA and immunohistochemical analysis of MCF-7 xenografts revealed significantly upregulated AMP-activated protein kinase (AMPK)-alpha-2 levels and activity in clinically dormant cells compared to estrogen-driven or acutely ED xenografts. Metformin, an AMPK activating drug approved for diabetes treatment, is currently being tested in clinical trials as an anti-cancer agent. In our model of clinically dormant disease, AMPK activation via metformin slowed ED-induced tumor regression and promoted tumor cell survival. Conversely, metformin treatment slowed estrogen-driven tumor growth, in agreement with prior observations that metformin slows growth of various tumor subtypes.
AMPK activation promotes survival of ER+ BC cells during ED. Thus, concurrent metformin and anti-estrogen therapies may promote survival of residual ER+ BC cells, which could increase risk of recurrence/progression.