Cancer Progression

Breast cancer awareness and screening programs have resulted in the majority of patients being diagnosed with early staged breast cancer.  Over 75% of newly diagnosed breast cancers are of the Estrogen Receptor-positive (ER-positive) subtype. ER-positive breast cancer is associated with less advanced disease and require estrogen to proliferate and survive.  The prognosis for many patients with ER-positive breast cancers are favorable due to its response to ER-targeted endocrine therapy. [26] The success of this initial line of therapy offers treatable benefits, however,  up to 40% of patients will have a relapse occurrence for endocrine therapy targets only ER-positive breast cancer cells and therefore may not eradicate all tumor cells. [27] 

 

The majority of deaths from breast cancer are due to ER-positive recurrent disease.  Approximately 62% of breast cancer deaths occur 5 to 20 years after initial diagnosis.  This suggests that latent breast micro metastases is a driver of the majority of breast cancer-associated mortalities. Our understanding of how breast cancers become metastatic as well as our knowledge of how disseminated breast cancer cells escape clinical detection, remaining dormant for years before reemerging as secondary incurable tumors remains a challenge. [41, 42] Circulating tumor cells can be detected in 36% of breast cancer patients that appeared to be disease-free and within stable remission for 7–22 years after undergoing mastectomy. [43]  Genomic DNA matching the original primary tumor was found in ~25% of people living with breast cancer up to 12 years following disease diagnosis. [44]

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Disease Progression.  As ER-positive breast cancers progress, hormone independent pathways may develop eliminating its reliance upon estrogen. Cells in the Tumor Micro Environment (TME) activate signal transduction pathways (i.e., TGFβ, EGFR/HER2 and PI3K/AKT/mTOR ) leading to the activation of the  Epithelial to Mesenchymal Transition (EMT), endocrine resistance, invasive aggressive disease and recurrence. ER expression is a major regulator actively suppressing processes associated with cell invasion and metastasis.[28, 29] ER expression is frequently inactivated, lost, or no longer driving tumorigenesis as breast cancers progress. Consequently, the decrease in ER expression abrogates the suppression of invasive and prometastatic genes.

 

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ER-positive Aggressive Recurring Cancers.  Due to mutation or modification [30-32], ER expression may continue to drive tumor progression [33-35] by coactivating with other pathways resulting in an aggressive phenotype. One pathway, often observed in more aggressive disease, is the significant ER crosstalk ability with nuclear factor kappa B (NFκB) signaling pathway. [36,37] Activation of NFκB in ER-positive tumors are associated with endocrine and chemotherapy resistance, aggressive and invasive characteristics, and cancer stem cell activation. Several complex crosstalk mechanisms have been described: 1) Mutual trans-repression, whereby ER represses NFκB activity and NFκB represses ER activity [38-40];  and 2) Mutual trans-activation.  Both mechanisms can lead to more aggressive ER-positive recurring cancers.​

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For Additional Medical and Scientific Information

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