Abstract P6-04-04: Upregulation of the androgen agonist prosaposin in aromatase inhibitor resistant breast cancer; mediation by the developmental protein HOXC11

Abstract Aromatase inhibitors work by abrogating the activity of the enzyme cyp 19 (Aromatase) which converts adrenal androgens into Estrogen within mammary adipose tissue. It is the synthesized steroid estrone that plays a pivotal role in promoting breast cancer growth in postmenopausal women. The development of resistance to AI therapy is still being elucidated, however studies have shown that tumour adaptability is of vital importance in the cancer cells ability to evade treatment. This may occur via the switch from estrogen dependent to estrogen-independent growth which manifests as the loss of positive estrogen receptor and progesterone receptor status. The levels of androgens generated by the adrenal glands of women decline gradually with age but are not dramatically impacted by menopause. As breast cancer cells are treated AI drugs to block the conversion of androstendione to estrogen these androgenic steroids will continue to circulate. Elucidation of the adaptive changes in the cancer cells in response to the altered steroid environment is therefore of interest. Research from this lab has identified the homeobox protein HOXC11 as an interacting partner of the steroid receptor coactivator SRC1 in endocrine resistance. HOXC11 target genes are undefined and so motif-mapping and RNA-seq experiments were undertaken to help elucidate the role of HOXC11 in the development of resistance and metastatic spread. From these studies we have identified Prosaposin (PSAP) as a putative HOXC11 regulated gene. PSAP is a known androgen agonist associated with metastatic potential in prostate cancer and endocrine resistance in breast cancer. Studies performed confirmed the ability of HOXC11 to regulate PSAP in AI resistant breast cancer. At a translational level PSAP is an extremely attractive target for clinical investigation due to its secretory nature which facilitates quantification from blood serum. Studies exploring the levels of secreted PSAP in resistant cell line models were undertaken and only the AI (letrozole) resistant cells had detectable levels of PSAP. Furthermore when we looked at levels of PSAP in breast cancer patients 18% had detectable amounts of the protein in their serum and the sample with the most elevated level was discovered to be from a patient who had suffered disease recurrence whilst undergoing AI therapy. High levels of serum PSAP also associated with strongly positive staining for androgen receptor in matched patient tissue. Survival analysis on a cohort of breast cancer patients (n = 680) suggests that in AI treated patients there is a trend indicting that positivity for androgen receptor may result in reduced disease-free survival. As a secreted protein PSAP will be readily detectable in breast cancer patients' serum from a simple blood sample and may indicate that the tumour cells are adapting to an androgen rich environment promoting disease progression. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P6-04-04.</jats:p

Coassociation of ERα and p160 proteins predicts resistance to endocrine treatment; SRC-1 is an independent predictor of breast cancer recurrence.

Abstract Abstract #3032 The p160 coactivators AIB1 and SRC-1 are known to play a critical role in modulating transcription in breast cancer cells in conjunction with ligand-bound estrogen receptor. The interactions of the p160 proteins with this nuclear receptor are also important in the development of resistance to endocrine treatments. Using quantitative coassociation immunofluorescent microscopy, the colocalisation of the p160s and ERα was increased in the LY2 endocrine resistant cell line following treatment with the anti-estrogen tamoxifen in comparison to the endocrine sensitive MCF-7 cell line. In cell cultures derived from patient tumours at the time of primary surgery prior to treatment, there was an increase in association of the coactivators with ERα following treatment with estrogen but dissociation was evident in the presence of tamoxifen. Immunohistochemical staining of a tissue microarray, constructed from 560 breast cancer patients, revealed that SRC-1 was a strong predictor of reduced disease-free survival, both in patients receiving adjuvant tamoxifen treatment and untreated patients (p&amp;lt;0.0001 and p=0.0111 respectively). AIB1 was not a significant independent predictor of disease recurrence. SRC-1 was assigned a hazard ratio of 2.12 when survival analysis using a Cox proportional hazards model was applied. Quantitative coassociation analysis of the p160 coactivators with ERα in the patient TMA revealed significantly stronger colocalisation of SRC-1 and ERα in patients who are known to have relapsed than those patients who did not recur (p=0.00001). This data suggests SRC-1 is pivotal in tumour aggressiveness and is a powerful predictor of progression of disease in breast cancer patients. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 3032.</jats:p