Isoform-specific expression of T-type voltage-gated calcium channels and estrogen receptors in breast cancer reveals specific isoforms that may be potential targets

Abstract

Purpose: T-type voltage-gated calcium channels (TTCCs) have been implicated as novel targets in breast cancer treatment; however, the knowledge of isoform-specific expression of TTCCs in the pathology of breast cancer remains limited. Although estrogen receptor blockers are clinically beneficial, patients often show resistance to these compounds. Interestingly, TTCCs are modulated by estrogen in the brain and heterologous expression systems; however, whether TTCCs and estrogen receptors (ERs) interact in breast tissue is unknown. In addition, the isoform specific expression of TTCCs and ERs in breast cancer subtypes has not been determined. Methods: We investigated the alterations in TTCC and ER gene isoforms, their co-occurrence and the association of alterations with patient survival in breast cancer and its subtypes by using The Cancer Genome Atlas (TCGA) dataset. To understand the functional roles of TTCC and ESR genes in breast cancer, we studied cell proliferation in the presence of a TTCC inhibitor and ER activator. Results: Our results from the TCGA dataset indicated differential alterations in TTCC isoform expression in patients with breast cancer, including downregulation of CACNA1G and upregulation of CACNA1H, and CACNA1I. Among ER isoforms, upregulation of ESR1 and downregulation of ESR2 were observed. Survival analysis indicated that ESR2 may be a potential target, because its downregulation was associated with shorter overall survival. Subtype specific survival analysis revealed CACNA1G, CACNA1H and ESR2 as potential novel targets in luminal type breast cancer. Alterations in ESR2 co-occurred with alterations in CACNA1H and CACNA1I, thus warranting investigation of potential crosstalk. Experimental data indicated that targeting both TTCCs and ESR2 may be beneficial for luminal type breast cancer. Conclusion: Our data provide novel insights into the altered expression of TTCC and ESR gene isoforms in breast cancer subtypes and suggest novel therapeutic targets.

Keywords

• Breast Cancer
• T-type calcium channels
• Estrogen receptors
• Isoforms