Endocrine resistance is still a major clinical problem in the treatment of breast cancer. Evidence suggests that dysregulation of growth factor signaling pathways contributes to endocrine resistance. Fibroblast growth factor 2 (FGF2) consists of a secreted form and several nuclear high molecular weight variants (HMW-FGF2). We previously showed that hormone-resistant tumors express higher HMW-FGF2 levels than endocrine-responsive variants and that HMW-FGF2-overexpression, in endocrine-responsive cells, induced tumor progression. Here, we aimed to explore the mechanisms underlying HMW-FGF2-induced hormone resistance. We show that HMW-FGF2-overexpression in T47D cell lines, induced hormone resistance, a dysregulation of the WNT signaling pathway (RNA-seq) and a decrease in estrogen and progesterone receptors, along with an increase in androgen receptor (AR) expression. We used endocrine-resistant cell lines expressing elevated HMW-FGF2 levels and their endocrine-responsive counterparts to target the AR and/or WNT pathways. Enzalutamide (ENZA; AR antagonist) was inhibited while dihydrotestosterone (DHT; AR agonist) increased cell proliferation only in resistant cell lines. Moreover, ICG-001 (WNT inhibitor) alone or combined with DHT reduced cell proliferation. In vivo, ENZA and LGK-974 (WNT inhibitor) inhibited T47D-HMW-FGF2 tumor growth, and the combined treatment induced a greater inhibition together with a reduction in the number of lung metastasis. To assess if there was a direct effect of WNT pathway activation on AR regulation we performed ChIP assays on TCF/LEF sites within the AR promoter. ICG-001 reduced the recruitment of β-catenin in the AR promoter. Our results suggest that, in endocrine-resistant cell lines with increased HMW-FGF2, an upregulated WNT pathway may modulate AR expression which, in turn, may guide tumor growth. In conclusion, targeting the WNT and/or AR pathway may be a promising therapy for endocrine-resistant breast carcinomas.