Abstract Breast cancer (BC) is the most frequently diagnosed malignancy and continues to be the second leading cause of cancer-related death in women in the United States. Dysregulation of Let-7 family microRNAs is observed in BC and associated with disease pathogenesis. Previously, we reported a significant increase in serum levels of resistin in BC patients as compared to the healthy individuals. Moreover, this increase was significantly greater in BC patients of African American background as compared to those of European descent. We also demonstrated that treatment of BC cells with resistin promoted their growth, aggressiveness, stemness and chemoresistance by inducing the expression and activation of STAT3. Here we present data to show that resistin induces STAT3 expression in BC cells in a LIN28A and Let-7a-dependent manner. Treatment of BC cells with resistin led to the most significant decrease in the expression of Let-7a among other Let-7 family members. Furthermore, resistin treatment also induced the expression of LIN28A at both transcript and protein levels and its silencing abrogated resistin-mediated Let-7a suppression. Let-7a restoration or LIN28A silencing abolished the resistin-induced growth, clonogenicity and sphere-forming ability of BC cells. Restoration of Let-7a suppressed the expression of several genes associated with growth, survival and stemness. Ingenuity Pathway Analysis suggested STAT3 as a putative central node associated with Let-7a-mediated gene regulation. Immunoblot analysis confirmed that Let-7a restoration dramatically suppressed basal as well as resistin-induced STAT3 expression. STAT3 regulation by Let-7a was further confirmed 3'UTR-reporter assay. Taken together, our findings demonstrate a novel resistin/LIN28A/Let-7a/STAT3 signaling axis regulating the growth and stemness phenotypes of BC cells. Citation Format: Sachin Kumar Deshmukh, Sanjeev K. Srivastava, Haseeb Zubair, Ajay P. Singh, Seema Singh. LIN28A-mediated repression of Let-7a is involved in resistin-induced STAT3 upregulation in breast cancer cells and supports growth and stemness properties [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5070.