Overcoming Resistance to Endocrine Therapy in Breast Cancer: New Approaches to a Nagging Problem

Abstract

In the majority of women, breast cancer progresses through increased transcriptional activity due to over-expressed oestrogen receptors (ER). Therapeutic strategies include: (i) reduction of circulating ovarian oestrogens or of peripherally produced oestrogen (in postmenopausal women) with aromatase inhibitors and (ii) application of selective ER modulators for receptor blockade. The success of these interventions is limited by the variable but persistent onset of acquired resistance and by an intrinsic refractiveness which manifests despite adequate levels of ER in about 50% of patients with advanced metastatic disease. Loss of functional ER leads to endocrine insensitivity, loss of cellular adhesion and polarity, and increased migratory potential due to trans-differentiation of the epithelial cancer cells into a mesenchymal-like phenotype (epithelial-mesenchymal transition; EMT). Multiple mechanisms contributing to therapeutic failure have been proposed: (i) loss or modification of ER expression including epigenetic mechanisms, (ii) agonistic actions of selective ER modulators that may be enhanced through an increased expression of co-activators, (iii) attenuation of the tamoxifen metabolism through expression of genetic variants of P450 cytochromes which leads to more or less active metabolites and (iv) increased growth factor signalling particularly through epidermal growth factor receptor activation of pathways involving keratinocyte growth factor, platelet-derived growth factor, and nuclear factor κB. In addition, the small non-coding microRNAs, recently recognized as critical gene regulators, exhibit differential expression in tamoxifen-sensitive versus resistant cell lines. Several studies suggest the potential of using these either as targets or as therapeutic agents to modulate EMT regulators as a means of reversing the aggressive metastatic phenotype by reversal of the EMT, with the added benefit of re-sensitization to anti-oestrogens.

Coordinate Enhancer Reprogramming by GATA3 and AP1 Promotes Phenotypic Plasticity to Achieve Breast Cancer Endocrine Resistance

“…Phenotypic plasticity, which can be enhanced by epigenetic reprogramming, is recognized as a general cause of therapy resistance in many cancers including lung cancer, prostate cancer, and others [3][4][5][6] . In ER+ luminal breast cancer, cell phenotypic transition during cancer progression is associated with the unsuccessful applications of tamoxifen and other endocrine agents that target ERα signaling 48 . To understand the underlying mechanism of endocrine resistance, we take advantage of a cellular model of endocrine resistance (TamR) that derive from MCF7P breast cancer cell line.…”

Sex Differences and Bone Metastases of Breast, Lung, and Prostate Cancers: Do Bone Homing Cancers Favor Feminized Bone Marrow?

“…For the future, many important questions remain regarding the influence of sexual dimorphism versus sex hormones on formation of bone metastases in the diverse disease we collectively call breast cancer. The role of estrogen ablation or blockade in promoting epithelial to mesenchymal transition with invasion ( 61 ), and in homing of breast cancer cells to bone, needs to be further studied as a sexually dimorphic variable, as does the potential for feminization of bone by long term estrogen administration that may favor bone metastasis. Bone metastases of breast cancer remain incurable, and the existing approaches for treatment such as bisphosphonates are non-specific, and do not account for the sex of the patient regardless of the primary tumor of origin ( 8 ).…”

Molecular Portrait of the Normal Human Breast Tissue and Its Influence on Breast Carcinogenesis

“…Moreover, CK5 has been proposed by some authors to be a marker that determines basal-like features of breast cancer, along with ER, PR, HER2, and EGFR [ 86 ]. Several of the most important markers with prognostic and therapeutic values in breast cancer are summarized in Table 1 [ 87 88 89 90 91 92 93 94 95 96 97 98 99 100 101 102 103 104 105 106 107 108 109 110 111 112 113 114 115 116 117 118 119 120 121 122 123 124 125 126 127 128 129 130 131 132 133 134 135 136 137 138 139 140 141 142 ].…”