Anti-Human epidermal growth factor receptor (HER) 2 therapy, trastuzumab for HER2 positive breast cancer patients improved their prognoses dramatically. However, there are some potentially trastuzumab-resistant breast cancer even in trastuzumab-naïve patients. Therefore, understanding of the molecular mechanism of trastuzumab resistance is strongly demanded. In this study, we hypothesized that micro RNA (miRNA) play important roles in trastuzumab treatment.
We performed comprehensive microRNA expression profiling of pre-treatment biopsy specimens in 83 HER2-positive breast cancer patients who underwent preoperative trastuzumab-chemo combined therapy. Then, let-7 family expression in cancer cells was elevated in non-pCR cases compared to pCR cases. Thus, we tried to elucidate molecular mechanisms associated with trastuzumab sensitivity and let-7 expression. We investigated their function in HER2-positive human breast cancer cell lines, trastuzumab-sensitive and -resistant. These two cell lines were used for gain/loss of function experiments. We also attempted to prove their correlations between serum let-7 change extracted from exosome and therapeutic effect using another 6 patients' blood sample.
The expression of let-7 family is regulated by LIN28 because it forms a double negative feedback loop with let-7. Let-7/LIN28 expression was down/up-regulated in BT474 (sensitive) cells by trastuzumab exposure, respectively, whereas the let-7/LIN28 expression was up/down-regulated in JIMT-1 (resistant) cells. Exogenous overexpression of let-7 in BT474 cell decreased trastuzumab sensitivity from 50% to 40% 6-day exposure of trastuzumab. Conversely, let-7-down-regulated JIMT-1 cells had down-regulated expression of let-7 family and recovered trastuzumab sensitivity from 0% to 20% (>2ug/mL).
The let-7/LIN28 regulatory circuit may have an important role in molecular mechanisms of trastuzumab-chemo therapy for HER2-positive breast cancer. Early assessment of this let-7/LIN28 response after treatment start might predict treatment outcome. We believe that modulation of this regulatory circuit might sensitize trastuzumab-resistant breast cancer cells.
Clinical trial identification
Legal entity responsible for the study
Chugai, Scientific research grant
M. Toi: Chugai Scientific research grant
All other authors have declared no conflicts of interest.