Abstract
Breast cancer (BC) is a heterogeneous disease characterized by different biopathological features, differential response to therapy and substantial variability in long-term-survival. BC heterogeneity recapitulates genetic and epigenetic alterations affecting transformed cell behavior. The estrogen receptor alpha positive (ERα+) is the most common BC subtype, generally associated with a better prognosis and improved long-term survival, when compared to ERα-tumors. This is mainly due to the efficacy of endocrine therapy, that interfering with estrogen biosynthesis and actions blocks ER-mediated cell proliferation and tumor spread. Acquired resistance to endocrine therapy, however, represents a great challenge in the clinical management of ERα+ BC, causing tumor growth and recurrence irrespective of estrogen blockade. Improving overall survival in such cases requires new and effective anticancer drugs, allowing adjuvant treatments able to overcome resistance to first-line endocrine therapy. To date, several studies focus on the application of loss-of-function genome-wide screenings to identify key (hub) “fitness” genes essential for BC progression and representing candidate drug targets to overcome lack of response, or acquired resistance, to current therapies. Here, we review the biological significance of essential genes and relative functional pathways affected in ERα+ BC, most of which are strictly interconnected with each other and represent potential effective targets for novel molecular therapies.
Highlights
Molecular heterogeneity and complexity make breast cancer (BC) one of the most aggressive tumors with a high mortality rate worldwide
BC, and in particular its ERα+ subtype is a heterogeneous pathology showing specific molecular features, where the endocrine resistance represents the major challenge for the management of patients affected by this disease
This cancer diversity depends on several genomic features involved in BC development and resistance; cancer progression is encoded by a variety of genes involved in several pathways, some belonging to several networks able to evolve in resistance mechanisms
Summary
Molecular heterogeneity and complexity make breast cancer (BC) one of the most aggressive tumors with a high mortality rate worldwide. The genome-wide CRISPR-Cas approach offers a wider knowledge of multiple active pathways and complex gene networks within cancer cells, giving the opportunity to characterize the genetic neoplastic landscape and highlight the functions of thousands of genes in the context of their essentiality for cell survival and proliferation. These genes, known as essential genes, can be considered potential candidates for the development of new pharmacological molecules or specific immunotherapy strategies able to counteract cancer driver genes activities. Given the crucial role of this receptor in the hormone-dependent tumors and its relevance as a therapeutic target, data reviewed here may uncover novel putative biomarkers and molecular targets for the development of new therapeutic strategies inactivating intrinsic oncogenic pathways or inhibiting physical ERα-coregulator interaction, to prevent and/or overcome resistance to current therapies
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