Sunday, 3 February 2013

FOXA1 is a gatekeeper, as well as a marker, for less aggressive breast cancer

Breast cancer is a complex disease, comprising of several recognised subtypes which can be distinguished by factors including the signature of the proteins within the tumour cells. Two such subtypes include luminal and basal breast cancer, the latter is more agressive and has a poorer prognosis for patients. Recent work has suggested that basal breast cancer cells may arise from luminal cells, although the mechanism for this is unclear.

A protein called FOXA1 may be the key to this transformation and Bernardo and colleges explore this in a recent paper in the journal Oncogene. The double helix is the basic structure of DNA (although exciting research from a group in Cambridge has identified four stranded DNA helices in cancer cells). Proteins and modifications to the double helix DNA compact it within the nucleus of the cell into a tightly wound structure known as chromatin. Like transcription factors such as twist, chromatin re-modellers including FOXA1, are capable of altering which genes are turned on and subsequently made into proteins. But chromatin re-modellers do this by altering the structure of chromatin, making the genes in DNA less or more accessible and in turn changing which proteins are made. Changing levels of FOXA1 in cells can therefore have dramatic results on the pattern of proteins, this can lead to changes in the function of those cells.

The group first took breast cancer cells which represent either luminal or basal subtypes and measured how much FOXA1 was present. In agreement with previous studies, luminal breast cancer cells had high levels of FOXA1, whereas this protein was almost undetectable in basal breast cancer cells. The researchers then took luminal breast cancer cells, artificially reduced the levels of FOXA1 and measured which genes were being transcribed (the first stage in making proteins of genes). This gives a fingerprint of all the genes turned on or off in a cell, called the "transcriptome". Interestingly, the loss of FOXA1 in luminal cells led to a decrease in luminal genes and an increase in basal genes switched on. This change from a luminal to basal gene signature with loss of FOXA1 expression was accompanied by increased motility and invasiveness of breast cancer cells.

FOXA1, therefore acts to prevent the conversion from a luminal to basal type breast cancer, and therefore limits the agressiveness of the tumour. This study supports the evidence that FOXA1 expression marks a less aggressive form of breast cancer with better prognosis, however it also suggests that efforts to target FOXA1 as a treatment for luminal breast cancers may have serious unwanted consequences such as increasing aggressiveness.

Mentioned Articles
Bernardo GM, Bebek G, Ginther CL, Sizemore ST, Lozada KL, Miedler JD, Anderson LA, Godwin AK, Abdul-Karim FW, Slamon DJ, Keri RA. (2013)
FOXA1 represses the molecular phenotype of basal breast cancer cells.
Oncogene. 2013 Jan 31;32(5):554-63. doi: 10.1038/onc.2012.62. Epub 2012 Mar 5.

Yamaguchi N, Ito E, Azuma S, Honma R, Yanagisawa Y, Nishikawa A, Kawamura M, Imai J, Tatsuta K, Inoue J, Semba K, Watanabe S. (2008)
FoxA1 as a lineage-specific oncogene in luminal type breast cancer.
Biochem Biophys Res Commun. 2008 Jan 25;365(4):711-7. Epub 2007 Nov 26. [Abstract and figures free]

Thorat MA, Marchio C, Morimiya A, Savage K, Nakshatri H, Reis-Filho JS, Badve S. (2008)
Forkhead box A1 expression in breast cancer is associated with luminal subtype and good prognosis.
J Clin Pathol. 2008 Mar;61(3):327-32. Epub 2007 Nov 23. [Abstract only free] (2013) Four-stranded ‘quadruple helix’ DNA structure proven to exist in human cells - Research - University of Cambridge. [online] Available at: [Accessed: 3 Feb 2013].

Phillips, T. & Shaw, K. (2008) Chromatin remodeling in eukaryotes. Nature Education 1(1)

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