BREAKING! Hong Kong Researchers Identify New Tumor-Suppressive Gene AKTIP That Can Be Utilized In Personalized Breast Cancer Treatments.

Researchers from the School of Biomedical Sciences, Li Ka Shing Faculty of Medicine, The University of Hong Kong have in a new study identified a new tumor-suppressive gene called AKTIP that can be utilized in personalized breast cancer treatments.


 
The key findings of the study showed that:
 
-AKTIP loss selectively promotes tumorigenesis of ERα-positive breast cancer cells
 
-AKTIP loss leads to ERα protein stabilization and JAK2/STAT3 activation
 
-Cullin 2-mediated ERα degradation is inhibited in AKTIP-depleted cells via CAND1
 
-AKTIP loss-induced endocrine resistance can be overcome by inhibiting JAK2/STAT3
 
Although recurrent deletion of 16q12.2 is observed in luminal breast cancer, the causal genomic alterations in this region are largely unknown.
 
The study team identified that loss of AKTIP gene, which is located on 16q12.2, drives tumorigenesis of estrogen receptor alpha (ERα)-positive, but not ERα-negative, breast cancer cells and is associated with poor prognosis of patients with ERα-positive breast cancer.
 
Interestingly, AKTIP-depleted tumors have increased ERα protein level and activity. Cullin-associated and neddylation-dissociated protein 1 (CAND1), which regulates the cullin-RING E3 ubiquitin ligases, protects ERα from cullin 2-dependent proteasomal degradation. Apart from ERα signaling, AKTIP loss triggers JAK2-STAT3 activation, which provides an alternative survival signal when ERα is inhibited. AKTIP-depleted MCF7 cells and ERα-positive patient-derived organoids are more resistant to ERα antagonists.
 
Significantly, the resistance can be overcome by co-inhibition of JAK2/STAT3.
The study findings highlight the subtype-specific functional consequences of AKTIP loss and provide a mechanistic explanation for the enriched AKTIP copy-number loss in ERα-positive breast cancer.
 
The study findings were published in the peer reviewed journal: Cell Reports
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01713-2
 
The study team discovered that somatic deletion of a tumor suppressor gene AKTIP promotes luminal breast cancer development and resistance to endocrine therapy.
 
At present, breast cancer is the most common cancer and the third leading cause of cancer death among women in Hong Kong, and can be classified into several molecular subtypes.
 
Each different subtype has distinct clinical characteristics, genetic profiles and treatment guidelines.
 
Although the disease can be hereditary with inherited mutations in genes such as BRCA1, the majority of the breast cancer cases are somatic resulted from non-inherited mutations that are acquired during one's lifetime.
 
The luminal breast cancer, which expresses a hormone receptor called estrogen receptor α (ERα), is the most common subtype and constitutes 60-70% of all breast cancer cases.
 
As a result of cancer cells expressing ERα which fuels cancer development, targeting ERα by therapeutic agents (endocrine therapy) is the cornerstone of management for luminal breast cancer.
 
Unfortunately, about one-third of luminal breast cancer patients who initially respond to endocrine therapy eventually develop resistance to the therapy.
 
Importantly, deletion of the AKTIP gene is observed in about 55% of luminal breast cancer cases. Despite the high occurrence, the consequence of the gene deletion was unknown.
 
Utilizing multi-omics and molecular biology approaches with breast cancer cell lines, clinical samples, mouse model and cancer patient-derived organoids, the study team made an intriguing discovery that loss of the AKTIP gene promotes breast cancer through increasing the protein expression level of ERα.
 
However, consistent with the pro-cancer consequences observed in these experimental models, an analysis of patient data showed that luminal breast cancer patients with AKTIP gene deletion had the worse survival!
 
Worryingly, it was found that breast cancer cells with AKTIP loss are resistant to endocrine therapy.
 
It was established that this endocrine resistance is due to a concurrent activation of another survival pathway JAK2/STAT3, which represents an alternative escape pathway utilized by the cancer cells when ERα is inhibited.
 
Progressing on this finding, the study team further found that blocking this alternative escape pathway by the addition of JAK2/STAT3 inhibitor can overcome the resistance.
 
The research findings identified a new driver aberration of luminal breast cancer and the therapeutic possibilities targeting breast tumors with AKTIP gene deletion.
 
Dr Lydia Cheung Wai-ting, Assistant Professor of School of Biomedical Sciences, Hong Long University told Breast Cancer News, "We present clear evidence that deletion of AKTIP is a prognostically and therapeutically relevant chromosomal mutation in luminal breast cancer. Our study findings showed that JAK2/STAT3 inhibitor can reverse the endocrine resistance caused by AKTIP deletion. Genomic data from tumor DNA profiling are increasingly guiding cancer care in which tailored therapy can be formulated based on the gene status of the cancer patient. This precision medicine approach can kill tumor cells efficiently with less toxic side effects. The incorporation of AKTIP gene status as predictive biomarker may refine the treatment strategy for luminal breast cancer."
 
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