The majority of breast cancer depend on estrogen receptor alpha (ERalpha) for growth and survival. Targeting ERalpha using selective ERalpha modulators, such as tamoxifen, has been a gold standard therapy for decades. However, about 40% of patients might acquire resistance or a recurrence of more aggressive tumors. The first approach of the thesis was to discover novel genetic factors or biomarkers that determine estrogen-dependent and -independent signaling of ERalpha, and the response of breast cancer cells to ERalpha-targeting therapy. For this, we employed a CRISPR/Cas9 genome-wide knockout screen using a breast cancer cell line. As a second goal of the work, we designed therapeutically relevant multidrug combinations to overcome drug-associated toxicity and resistance for ERalpha+ breast cancer. Collectively, in two independent chapters, we describe the multidisciplinary approaches used to solve the proposed current clinical challenges.