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Simple Summary  Breast cancers are broadly classified into two subtypes: estrogen receptor-positive and estrogen receptor-negative. Approximately 70% of breast cancers are estrogen receptor-positive and this type of breast cancer is more common in postmenopausal women. Estrogen receptor-positive breast cancers are treated with a class of drugs called anti-estrogens. While the majority of tumors respond to this class of drugs, disease recurs in approximately 30% of cases, sometimes even 20 years after initial diagnosis. This review highlights efforts to understand why tumors recur despite effective treatments and outcome of these efforts in the development of new combination therapies. At least three new types of combination therapies that delay progression of recurrent tumors are in clinical use.    Abstract  Signaling from estrogen receptor alpha (ERα) and its ligand estradiol (E2) is critical for growth of ≈70% of breast cancers. Therefore, several drugs that inhibit ERα functions have been in clinical use for decades and new classes of anti-estrogens are continuously being developed. Although a significant number of ERα+ breast cancers respond to anti-estrogen therapy, ≈30% of these breast cancers recur, sometimes even after 20 years of initial diagnosis. Mechanism of resistance to anti-estrogens is one of the intensely studied disciplines in breast cancer. Several mechanisms have been proposed including mutations in  ESR1 , crosstalk between growth factor and ERα signaling, and interplay between cell cycle machinery and ERα signaling.  ESR1  mutations as well as crosstalk with other signaling networks lead to ligand independent activation of ERα thus rendering anti-estrogens ineffective, particularly when treatment involved anti-estrogens that do not degrade ERα. As a result of these studies, several therapies that combine anti-estrogens that degrade ERα with PI3K/AKT/mTOR inhibitors targeting growth factor signaling or CDK4/6 inhibitors targeting cell cycle machinery are used clinically to treat recurrent ERα+ breast cancers. In this review, we discuss the nexus between ERα-PI3K/AKT/mTOR pathways and how understanding of this nexus has helped to develop combination therapies.

Nexus between PI3K/AKT and Estrogen Receptor Signaling in Breast Cancer