Liver Kinase B1—A Potential Therapeutic Target in Hormone-Sensitive Breast Cancer in Older Women

Abstract

Background: The role of liver kinase B1 (LKB1), a serine/threonine kinase, has been described in the development of PeutzJagher’s syndrome, where a proportion (~45%) of patients have developed breast cancer in their lifetime. Cell line studies have linked LKB1 with oestrogen receptors (ER) and with the Adenosine monophosphate-activated protein kinase (AMPK) pathway for energy metabolism. However, limited studies have investigated protein expression of LKB1 in tumour tissues and its intracellular relationships. This study aimed to investigate the intracellular molecular relationships of LKB1 in older women with early operable primary breast cancer and its correlation with long-term clinical outcome. Methods: Between 1973 and 2010, a consecutive series of 1758 older (≥70 years) women with T0-2N0-1M0 breast carcinoma were managed in a dedicated facility. Of these, 813 patients underwent primary surgery, and 575 had good quality tumour samples available for tissue microarray construction. LKB1 was assessed in 407 cases by indirect immunohistochemistry (IHC). Tumours with 30% or more of cells with cytoplasmic LKB1 expression were considered positive. LKB1 expression was compared with tumour size, histological grade, axillary lymph node stage, ER, PgR, EGFR, HER2, HER3, HER4, BRCA1&2, p53, Ki67, Bcl2, Muc1, E-Cadherin, CD44, basal (CK5, CK5/6, CK14 and CK17) and luminal (CK7/8, CK18 and CK19) cytokeratins, MDM2 and MDM4, and correlated with long-term clinical outcome. Results: Positive LKB1 expression was seen in 318 (78.1%) patients, and was significantly associated with high tumour grade, high Ki67, over-expression of HER2, VEGF, HER4, BRCA2, MDM2 and negative expression of CD44 (p < 0.05). There was no significant correlation with tumour size, axillary lymph node status, ER, PgR, p53, basal or luminal cytokeratins, Bcl2, Muc1, EGFR, HER3, MDM4, E-cadherin and BRCA1. LKB1 did not show any significant influence on survival in the overall population; however, in those patients receiving adjuvant endocrine therapy for ER positive tumours, those with positive LKB1 had significantly better 5-year breast cancer specific survival when compared to those without such expression (93% versus 74%, p = 0.03). Conclusion: LKB1 expression has shown association with poor prognostic factors in older women with breast cancer. However, LKB1 expression appears to be associated with better survival outcome among those patients receiving adjuvant endocrine therapy. Further research is required to explore its potential role as a therapeutic target.

Patterns of biomarker expression in patients treated with primary endocrine therapy – a unique insight using core needle biopsy tissue microarray

“…LKB1 is a tumour suppressor gene, of which there is little research in the setting of older women. Studies have shown that LKB1 can inhibit the aromatase enzyme with the AMP-activated protein kinase, supporting its potential role in prediction of response to primary endocrine therapy [32,33]. In a recent analysis of all patients undergoing surgery within the current cohort of older women described in this present study, older women had higher expression of LKB1 compared to a younger cohort [32].…”

“…Studies have shown that LKB1 can inhibit the aromatase enzyme with the AMP-activated protein kinase, supporting its potential role in prediction of response to primary endocrine therapy [ 32 , 33 ]. In a recent analysis of all patients undergoing surgery within the current cohort of older women described in this present study, older women had higher expression of LKB1 compared to a younger cohort [ 32 ]. LKB1 expression was associated with better survival among patients receiving adjuvant endocrine therapy, but TTP was not reported.…”

“…The authors hypothesise that the contradictory results in these two studies may be related to the context of the studies. In the paper by Syed et al [ 32 ], LKB1 was measured in surgical samples; in the present study, LKB1 has been measured on CNB samples in patients treated by PET. There could be fundamental differences between these two groups of patients due to treatment selection; however, further work is required to confirm this.…”

Biology of primary breast cancer in older women beyond routine biomarkers

“…Four studies made a direct comparison between measurement of biomarkers in an older compared to a younger cohort (Table 1) [9,[16][17][18][19]. The remaining eight studies measured a biomarker in an older cohort alone (Table 2) [20][21][22][23][24][25][26][27].…”

Treatment Strategies and Survival Outcomes in Breast Cancer

“…Given this, and other needs to appropriately select treatments, including primary and adjuvant therapies in this challenging population, biomarker studies play a very important role in translational research. Three such biomarkers-LKB1 [7] and cytoplasmic cyclin E [8] (poor prognostic in the older (>70 years) population), and HDAC5 [9] (poor prognostic in the very young (<35 years) patients)-have been found to be associated with age. Furthermore, other conventional and emerging prognostic and predictive factors were investigated and reported in this Special Issue.…”