Development of steroidal molecules for targeted breast cancer therapy: Endocrine resistance and innovative drug design.

Endocrine therapy has stood as a fundamental pillar in addressing hormone receptor-positive breast cancer. Nevertheless, the emergence of resistance to these therapies poses a significant and ongoing clinical hurdle. Of late, there is a growing interest toward investigating the role of steroidal molecules in treatment of endocrine resistant breast cancer. The intricate and fascinating structural framework of the steroidal nucleus has drawn considerable scientific attention globally to devise novel and effective derivatives for combating breast cancer. Apart from its structural appeal, the multi-target oriented steroidal nucleus empowers researchers to design and develop a wide range of compounds for use in the treatment of breast cancer. Steroids remain a cornerstone of breast cancer clinical setting, offering significant advantages over non-steroidal counterparts as they act through multiple mechanisms like irreversibly inactivating the aromatase enzyme, downgrading estrogen receptors and simultaneously reducing estrogen and androgen levels through sulfatase inhibition. It is implied that the development of novel multifunctional steroidal molecules with complementary mechanisms could positively transform hormone-dependent cancer therapy by ensuring prolonged estrogen suppression and reduced resistance risk. This comprehensive review article provides an overview of the underlying complex mechanisms responsible for the development of resistance to endocrine therapies. Furthermore, it aims to explore the potential therapeutic possibilities that steroidal molecules may offer within this resistant context.