Abstract P6-04-04: Upregulation of the androgen agonist prosaposin in aromatase inhibitor resistant breast cancer; mediation by the developmental protein HOXC11
Authors: McIlroy M , Hao Y , Bane FT , Young L , O'Gaora P 
Published: August 2014

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.