Mechanism of hormone resistance in breast cancer
Breast cancer is the most common cancer in women, with endocrine hormone therapy significantly improving survival in estrogen receptor-positive (ER+) cases. However, resistance to treatment leads to relapses. This study examines genomic alterations in about 200 therapy-resistant and sensitive breast cancer samples using whole exome (WES) and whole transcriptome sequencing (WTS). We developed resistant cell lines from sensitive ones (MCF7, T47D) for tamoxifen, fulvestrant, and estrogen deprivation resistance. An ongoing study includes in vitro and in vivo analysis using an orthotopic mouse model to explore novel genes' roles in resistance, aiming to develop targeted therapies for resistant breast cancer.
Figure: Schematic representation of the project with establishment of orthotopic breast cancer mouse model
Identifying the targets of progesterone in breast cancer
A randomized study at Tata Memorial Centre found that pre-operative progesterone improves disease-free and overall survival in patients with node-positive breast cancer, irrespective of progesterone receptor (PR) status (J Clin Oncol, 2011. 29(21): p. 2845-51). However, the underlying mechanism remains unclear. We conducted proteome profiling of PR-positive and PR-negative breast cancer cells using a phospho-kinase array. Our results indicate progesterone induces dephosphorylation of EGFR, AKT, and ERK1/2, inhibiting cell invasion and migration independent of PR status. Deep sequencing of small RNA revealed that progesterone up-regulates miR-129-2, which targets the 3’UTR of PR, suggesting a feedback mechanism. Further integrated analysis identified dual-phase regulation of SGK1: direct transcriptional activation in PR-positive cells and miR-29a/miR-101-1-mediated regulation in PR-negative cells. We also observed regulation involving long non-coding RNAs (lncRNAs). This up-regulation activates the metastasis suppressor gene NDRG1 via AP-1 network genes, inhibiting invasion and migration. Our model explains progesterone's action in breast cancer, highlighting potential targets for monitoring hormone therapy responses.
Figure: A model depicting the action of progesterone in breast cancer.
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