PI3K/Akt/mTOR signalling pathway activation in patients with ER‑positive, metachronous, contralateral breast cancer treated with hormone therapy

Abstract

Oestrogen receptor (ER)-positive, metachronous, contralateral breast cancer (MCBC) sometimes develops during or soon after completion of hormone therapy (HT), but it is uncertain whether it is HT-resistant. We examined the association between ER-positive second cancer and activation of the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) pathways, which are associated with HT resistance. We examined the treatment-free interval (time after completion of HT for initial cancer) in 41 patients with ER-positive MCBC with a history of adjuvant HT for initial cancer (HT group), and initial-to-second period duration (time after operation of initial cancer to onset of second cancer) in 17 patients with ER-positive MCBC in whom adjuvant HT was not applied to the initial tumour (control group or no HT group). Phosphorylated S6 (pS6) and phosphorylated MAPK (pMAPK) were used as indicators of PI3K/Akt/mTOR and MAPK pathway activity, respectively. Tumours were classified as showing negative, positive or strongly positive staining, and the correlation between staining and treatment-free interval or initial-to-second period duration was evaluated using the Spearman's rank correlation coefficient (ρ). Treatment-free interval and pS6 staining showed a negative correlation (ρ=-0.5355; P=0.0003) in the HT group. There was no correlation between initial-to-second period duration and pS6 staining in the no HT group (ρ=-0.0814; P=0.756). There was no correlation between pMAPK signalling and the treatment-free interval in the HT group (ρ=-0.1560; P=0.330) or the initial-to-second period duration in the no HT group (ρ=-0.0116; P=0.965). Development of a second ER-positive cancer during or soon after completion of HT for the initial cancer may be associated with activation of the PI3K/Akt/mTOR pathway. Care should be taken during follow-up and when selecting adjuvant therapy for second cancer.

First in class dual MDM2/MDMX inhibitor ALRN-6924 enhances antitumor efficacy of chemotherapy in TP53 wild-type hormone receptor-positive breast cancer models

“…mTOR pathway is one of the classical canonical pathways involved in cancer cell proliferation and metastasis [ 44 ]. Emerging evidence has demonstrated that the mTOR pathway has been associated with endocrine therapy resistance [ 45 ], especially in metastatic breast cancers [ 46 ]. By inhibiting this pathway, it has been shown to prevent resistance and restore sensitivity in hormone-positive breast cancers [ 47 ].…”

SP3 is associated with migration, invasion, and Akt/PKB signalling in MDA‐MB‐231 breast cancer cells

“…Surprisingly, silencing SP3 inhibited the active phosphorylation of Akt at Ser473 and Thr308 (Figure 3A), which mediates the activity of Akt signalling in breast cancer. [ 25 ] Then, we investigated whether SP3 is driving MDA‐MB‐231 migration and invasion. As shown in Figure 3C, silencing SP3 using siRNA in MDA‐MB‐231 drives mesenchymal–epithelial transition using phase‐contrast images.…”

Next-generation sequencing revealed recurrent ZFPM1 mutations in encapsulated papillary carcinoma of the breast

“…The frequency of mutations of PIK3CA and AKT1 in EPCs is consistent with previous reports in breast papillary neoplasms 31 , 32 . Either elevated PI3K activity as a result of PIK3CA mutations or downstream AKT activation could cause an oncogenic transformation in mammary epithelial cells and the formation of heterogeneous mammary tumors in vivo 33 – 35 . As downstream genes of PI3K-AKT signaling, ULK1 gene could encode an autophagy initiator protein, and its mutation was detected in 4.8% of our EPCs.…”