Tamoxifen resistance in breast cancer elucidating mechanisms

About 80% of the breast cancer patients express oestrogen receptor α (ERα) in their tumours, which is essential for normal mammalian gland development and breast cancer development and progression.Tamoxifen is the accepted therapy for patients with estrogen receptor-α (ERα)-positive breast cancer.She hopes to one day be an oncologist and clinician-scientist, and is looking forward to her final year of medical school in 2016.

sudan online chat dating site - Tamoxifen resistance in breast cancer elucidating mechanisms

As a result, breast cancer cells are able to destroy or export toxic oxidation products leading to increased survival from tamoxifen-induced oxidative damage.

These responses in cancer cells also occur in breast tumors of tamoxifen-treated mice.

Breast cancer cells responded to tamoxifen-induced oxidation by increasing Nrf2 expression and subsequent activation of the anti-oxidant response element (ARE).

This increased the transcription of anti-oxidant genes and multidrug resistance transporters.

Unfortunately the clinical benefit is limited due to intrinsic and acquired drug resistance.

Here using integrated genomic and functional studies, we report that amplification and/or overexpression of COPS5 (CSN5/JAB1) confers resistance to tamoxifen.

Amplification and overexpression of COPS5, a catalytic subunit of the COP9 complex, is present in about 9% of the ERα primary breast cancer and more frequently (86.7%, 26/30) in tamoxifen-refractory tumours.

Overexpression of COPS5, through its isopeptidase activity, leads to ubiquitination and proteasome-mediated degradation of NCo R, a key corepressor for ERα and tamoxifen-mediated suppression of ERα target genes.

The principal aim is to review the current literature on the mechanisms underpinning tamoxifen resistance and emerging strategies to overcome this challenge, with a focus on those with the greatest translational potential.

Numerous molecular mechanisms of tamoxifen resistance have been proposed and investigated.

Treatment success is primarily dependent on the presence of the estrogen receptor (ER) in the breast carcinoma.

Tags: , ,