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 subtype has
distinct clinical characteristics, genetic profiles and treatment
guidelines.
While 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. Because the cancer cells express ERα
which fuels cancer development, targeting ERα by therapeutic agents
(endocrine therapy) is the cornerstone of management for luminal breast
cancer.
However,
one-third of luminal breast cancer patients who initially respond to
endocrine therapy eventually develop resistance to the therapy. 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.
Through
multi-omics and molecular biology approaches using breast cancer cell
lines, clinical samples, mouse model and cancer patient-derived
organoids, the team made an intriguing discovery that loss of the AKTIP gene promotes breast cancer through increasing the protein expression level of ERα.
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 has worse survival. Importantly, breast cancer cells with AKTIP loss
are resistant to endocrine therapy. 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.
Building
on this finding, the team further found that blocking this alternative
escape pathway by the addition of JAK2/STAT3 inhibitor can overcome the
resistance.
This
study identified a new driver aberration of luminal breast cancer and
the therapeutic possibilities targeting breast tumors with AKTIP gene deletion. ‘We present clear evidence that deletion of AKTIP is
a prognostically and therapeutically relevant chromosomal mutation in
luminal breast cancer. Our findings that JAK2/STAT3 inhibitor can
reverse the endocrine resistance caused by AKTIP deletion need to be further investigated.
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,’ explained the senior author.
https://www.cell.com/cell-reports/fulltext/S2211-1247(22)01713-2
http://sciencemission.com/site/index.php?page=news&type=view&id=publications%2Faktip-loss-is-enriched&filter=22