Aberrant calcium signalling downstream of mutations in TP53 and the PI3K/AKT pathway genes promotes disease progression and therapy resistance in triple negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is characterized as an aggressive form of breast cancer (BC) associated with poor patient outcomes. For the majority of patients, there is a lack of approved targeted therapies. Therefore, chemotherapy remains a key treatment option for these patients, but significant issues around acquired resistance limit its efficacy. Thus, TNBC has an unmet need for new targeted personalized medicine approaches. Calcium (Ca²⁺) is a ubiquitous second messenger that is known to control a range of key cellular processes by mediating signalling transduction and gene transcription. Changes in Ca²⁺ through altered calcium channel expression or activity are known to promote tumorigenesis and treatment resistance in a range of cancers including BC. Emerging evidence shows that this is mediated by Ca²⁺ modulation, supporting the function of tumour suppressor genes (TSGs) and oncogenes. This review provides insight into the underlying alterations in calcium signalling and how it plays a key role in promoting disease progression and therapy resistance in TNBC which harbours mutations in tumour protein p53 (TP53) and the PI3K/AKT pathway.

Keywords: PI3K/AKT pathway; TP53; Triple-negative breast cancer; calcium.

Figure 1

Summary of wild-type and mutant p53 calcium mediated cell death processes. (A) Wild-type p53: (1) induces apoptosis by different cellular stresses such as hypoxia and chemotherapy; (2) mediates an increase in ER Ca²⁺ through SERCA; (3) promotes ER Ca²⁺ transfer to the mitochondria resulting in a Ca²⁺ overloading activated caspase 3 and thus PARP; and (4) mediates apoptosis through an induction in TRPC6 expression and (5) associated Ca²⁺ influx. (B) (1) Mutations in TP53 result in a loss of function; (2) TP53 fails to induce SERCA; (3) this leads to reduced mitochondrial Ca²⁺ promoting apoptotic resistance; (4) ORAI3 is increased in TNBC, promoting Ca²⁺-mediated increase in serum and glucocorticoid-induced protein kinase-1 (SGK-1) inducing TP53 degradation and (5) increased S100 calcium-binding protein P (S100P) also induces TP53 degradation. Both enhance cell survival. ER: Endoplasmic reticulum; PARP: poly(ADP-Ribose) polymerase; SERCA: sarco/endoplasmic reticulum Ca²⁺ ATPase.

Figure 2

The role of TP53 in the PI3K/AKT signalling pathway. RTKs are activated by hormones and growth factors, leading to the recruitment and phosphorylation of PI3K. PDK1 is then recruited to AKT at the PH domain. Cell cycle, survival, migration and apoptosis regulation occur as a result of AKT signalling pathway activation. AKT is also activated by mTORC₂ and mTORC₁ is activated by phosphorylated AKT, promoting protein translation and cell growth. Hdm2 regulates P53 in normal healthy cells, resulting in low levels. P53 regulates PTEN, inhibiting PI3K phosphorylation and AKT activation. AKT may enhance the function of Hdm2 and PTEN may prevent P53 degradation via AKT pathway inhibition. P53 binds to PI3K to inhibit PIK3CA and mutations in TP53 may result in PIK3CA hyperactivation and subsequent PI3K signalling pathway activation. AKT: Protein kinase B; PTEN: phosphatase and tensin homolog.

Figure 3

Role of calcium store release via IP3R in mediating apoptosis and its regulation via PI3K/AKT pathways. (A) (1) G protein-coupled receptors (GPCR), Receptor tyrosine kinase (RTK) and others, along with cellular stress, can induce PLC, PIP2 and IP3, leading to activation of IP3R channels on the ER, promoting Ca²⁺ store release. (3) This mediates Ca²⁺ transfer to the mitochondria inducing apoptosis. (4) PTEN also plays a role in mediating this pathway in part by blocking anti-apoptotic oncogene AKT. (B) (1) Activation of oncogenes such as AKT inhibits IP3R Ca²⁺ release from ER stores under chemotherapy and GPCR activation. (2) This is achieved by phosphorylating IP3R and (3) reducing Ca²⁺ transfer to the mitochondria, enabling apoptotic resistance. (4) PTEN loss is common in TNBC, enabling AKT signalling. (5) NCS-1 is increased in TNBC, promoting IP3R inactivation as well. (6) SOCE is mediated after store release via IP3R; channels such as ORAI and TRP that are activated have increased expression in TNBC and are linked to promoting EMT and thus chemotherapy resistance. RTK: Receptor tyrosine kinase; Orai: calcium release-activated calcium channel protein; PLC: phospholipase C; GPCR: G protein-coupled receptors.